Bio

Academic Appointments


Administrative Appointments


  • Director, Nancy Pritzker Laboratory (1999 - Present)
  • co-Director, Stanford Institute for Neuro-Innovation and Translational Neurosciences (2008 - 2013)
  • Associate Chair, Dept. of Psychiatry & Behavioral Sciences (2008 - Present)
  • Deputy Director, Stanford Neurosciences Institute (2013 - Present)

Honors & Awards


  • Young Investigator Award, Society for Neuroscience (1993)
  • Daniel Efron Award, American College of Neuropsychopharmacology (1998)
  • Distinguished Alumni Award, Stanford Medical School (1998)
  • Associate, Neurosciences Research Program (1999-2006)
  • International Prize in Neuroscience, Dargut and Milena Kemali Foundation (2000)
  • Basic Neuroscience Research Award, Collegium Internationale Neuropsychopharmacologicum-Lilly (2002)
  • Member, National Academy of Medicine (2004)
  • Fellow, American Academy of Arts and Sciences (2005)
  • Fellow, American Association for the Advancement of Science (2009)
  • Julius Axelrod Mentorship Award, American College of Neuropsychopharmacology (2011)
  • Medical Research Award in Neuropsychiatry, Robert and Claire Pasarow Foundation (2011)
  • Member, National Academy of Sciences (2011)
  • Julius Axelrod Prize, Society for Neuroscience (2016)

Boards, Advisory Committees, Professional Organizations


  • Program Committee, Society for Neuroscience (1999 - 2004)
  • Scientific Advisory Board, Renovis, Inc. (2000 - 2008)
  • Scientific Advisory Board, Merck, Inc. (2000 - 2008)
  • Scientific Council, NARSAD, Brain and Behavior Research Foundation (2001 - Present)
  • Council, Society for Neuroscience (2006 - 2010)
  • Scientific Advisory Board, Seaside Therapeutics, Inc. (2006 - 2015)
  • Scientific Advisory Board, Stanley Center for Psychiatric Research, Broad Institute, Harvard/MIT (2006 - 2016)
  • Scientific Advisory Board, Pfizer, Inc. (2008 - 2011)
  • Board of Directors, The Brain Research Foundation (2010 - Present)
  • Scientific Advisory Board, International Mental Health Research Organization (2010 - Present)
  • Council, American College of Neuropsychopharmacology (2012 - 2015)
  • Scientific Advisory Board, Cure Alzheimer's Fund (2012 - Present)
  • co-Founder/Scientific Advisory Board, Circuit Therapeutics, Inc. (2012 - Present)
  • Scientific Advisory Board, Neurocampus, Bordeaux, France (2013 - Present)

Research & Scholarship

Current Research and Scholarly Interests


Long-lasting activity-dependent changes in the efficacy of synaptic transmission play an important role in the development of neural circuits and may mediate many forms of learning and memory. Work from my laboratory over the last 10 years has demonstrated that there are a variety of related but mechanistically distinct forms of synaptic plasticity. A major goal of my laboratory is to elucidate both the specific molecular events that are responsible for the triggering of these various forms of synaptic plasticity and the exact modifications in synaptic proteins that are responsible for the observed, long-lasting changes in synaptic efficacy. To accomplish this we use cellular electrophysiological recording techniques to examine synaptic plasticity in a variety of different in vitro preparations including thin slices of various regions of the rodent brain and primary neurons in culture. We also use cell biological and molecular techniques to examine the activity-dependent modulation of neurotransmitter receptors and to express dominant negative forms of various synaptic proteins so that their exact functions can be determined. An additional complementary approach has involved examining synaptic physiology and synaptic plasticity in various mutant mouse lines lacking specific synaptic proteins.

A related but independent area of research in my laboratory is the elucidation of the synaptic action of drugs of abuse such as the psychostimulants cocaine and amphetamine. Toward this end, we have developed in vitro slice preparations of the nucleus accumbens and ventral tegmental area, brain regions which are thought to mediate several of the behavioral effects of drugs of abuse. We have characterized a novel form of synaptic plasticity in the nucleus accumbens and have done an extensive pharmacological characterization of the synaptic effects of dopamine, cocaine, and amphetamine. Currently we are examining in more detail the underlying mechanisms of dopamine's actions and determining how chronic treatment with drugs of abuse affect the synaptic responses of nucleus accumbens and ventral tegmental area cells. Because chronic exposure to drugs of abuse elicit long-term adaptive changes in critical neural circuits, it is hoped that the knowledge gained from the work on the molecular mechanisms underlying synaptic plasticity will provide important clues to the molecular mechanisms underlying the development of tolerance, dependence and addiction.

Teaching

2016-17 Courses


Graduate and Fellowship Programs


Publications

All Publications


  • Input- and Output-Specific Regulation of Serial Order Performance by Corticostriatal Circuits NEURON Rothwell, P. E., Hayton, S. J., Sun, G. L., Fuccillo, M. V., Lim, B. K., Malenka, R. C. 2015; 88 (2): 345-356
  • Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping CELL Beier, K. T., Steinberg, E. E., DeLoach, K. E., Xie, S., Miyamichi, K., Schwarz, L., Gao, X. J., Kremer, E. J., Malenka, R. C., Luo, L. 2015; 162 (3): 622-634
  • Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping. Cell Beier, K. T., Steinberg, E. E., DeLoach, K. E., Xie, S., Miyamichi, K., Schwarz, L., Gao, X. J., Kremer, E. J., Malenka, R. C., Luo, L. 2015; 162 (3): 622-634

    Abstract

    Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors.

    View details for DOI 10.1016/j.cell.2015.07.015

    View details for PubMedID 26232228

  • Optogenetics and the circuit dynamics of psychiatric disease. JAMA Deisseroth, K., Etkin, A., Malenka, R. C. 2015; 313 (20): 2019-2020

    View details for DOI 10.1001/jama.2015.2544

    View details for PubMedID 25974025

  • Illuminating circuitry relevant to psychiatric disorders with optogenetics CURRENT OPINION IN NEUROBIOLOGY Steinberg, E. E., Christoffel, D. J., Deisseroth, K., Malenka, R. C. 2015; 30: 9-16

    Abstract

    The brain's remarkable capacity to generate cognition and behavior is mediated by an extraordinarily complex set of neural interactions that remain largely mysterious. This complexity poses a significant challenge in developing therapeutic interventions to ameliorate psychiatric disease. Accordingly, few new classes of drugs have been made available for patients with mental illness since the 1950s. Optogenetics offers the ability to selectively manipulate individual neural circuit elements that underlie disease-relevant behaviors and is currently accelerating the pace of preclinical research into neurobiological mechanisms of disease. In this review, we highlight recent findings from studies that employ optogenetic approaches to gain insight into normal and aberrant brain function relevant to mental illness. Emerging data from these efforts offers an exquisitely detailed picture of disease-relevant neural circuits in action, and hints at the potential of optogenetics to open up entirely new avenues in the treatment of psychiatric disorders.

    View details for DOI 10.1016/j.conb.2014.08.004

    View details for Web of Science ID 000348337600002

  • Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science Schwartz, N., Temkin, P., Jurado, S., Lim, B. K., Heifets, B. D., Polepalli, J. S., Malenka, R. C. 2014; 345 (6196): 535-542

    Abstract

    Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1-triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.

    View details for DOI 10.1126/science.1253994

    View details for PubMedID 25082697

  • Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens SCIENCE Schwartz, N., Temkin, P., Jurado, S., Lim, B. K., Heifets, B. D., Polepalli, J. S., Malenka, R. C. 2014; 345 (6196): 535-542
  • Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin NATURE Doelen, G., Darvishzadeh, A., Huang, K. W., Malenka, R. C. 2013; 501 (7466): 179-?

    Abstract

    Social behaviours in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviours, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin acts as a social reinforcement signal within the nucleus accumbens core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the nucleus accumbens receives oxytocin-receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-hydroxytryptamine; 5-HT) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. Furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-HT1B receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-HT in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.

    View details for DOI 10.1038/nature12518

    View details for Web of Science ID 000324244900032

    View details for PubMedID 24025838

  • Leucine-Rich Repeat Transmembrane Proteins Are Essential for Maintenance of Long-Term Potentiation NEURON Soler-Llavina, G. J., Arstikaitis, P., Morishita, W., Ahmad, M., Suedhof, T. C., Malenka, R. C. 2013; 79 (3): 439-446

    Abstract

    Leucine-rich repeat transmembrane proteins (LRRTMs) are synaptic cell adhesion molecules that trigger excitatory synapse assembly in cultured neurons and influence synaptic function in vivo, but their role in synaptic plasticity is unknown. shRNA-mediated knockdown (KD) of LRRTM1 and LRRTM2 in vivo in CA1 pyramidal neurons of newborn mice blocked long-term potentiation (LTP) in acute hippocampal slices. Molecular replacement experiments revealed that the LRRTM2 extracellular domain is sufficient for LTP, probably because it mediates binding to neurexins (Nrxs). Examination of surface expression of endogenous AMPA receptors (AMPARs) in cultured neurons suggests that LRRTMs maintain newly delivered AMPARs at synapses after LTP induction. LRRTMs are also required for LTP of mature synapses on adult CA1 pyramidal neurons, indicating that the block of LTP in neonatal synapses by LRRTM1 and LRRTM2 KD is not due to impairment of synapse maturation.

    View details for DOI 10.1016/j.neuron.2013.06.007

    View details for Web of Science ID 000323085100006

  • Diverging neural pathways assemble a behavioural state from separable features in anxiety NATURE Kim, S., Adhikari, A., Lee, S. Y., Marshel, J. H., Kim, C. K., Mallory, C. S., Lo, M., Pak, S., Mattis, J., Lim, B. K., Malenka, R. C., Warden, M. R., Neve, R., Tye, K. M., Deisseroth, K. 2013; 496 (7444): 219-223

    Abstract

    Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections-to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area-each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.

    View details for DOI 10.1038/nature12018

    View details for Web of Science ID 000317346300041

  • LTP Requires a Unique Postsynaptic SNARE Fusion Machinery NEURON Jurado, S., Goswami, D., Zhang, Y., Minano Molina, A. J., Suedhof, T. C., Malenka, R. C. 2013; 77 (3): 542-558

    Abstract

    Membrane fusion during exocytosis is mediated by assemblies of SNARE (soluble NSF-attachment protein receptor) and SM (Sec1/Munc18-like) proteins. The SNARE/SM proteins involved in vesicle fusion during neurotransmitter release are well understood, whereas little is known about the protein machinery that mediates activity-dependent AMPA receptor (AMPAR) exocytosis during long-term potentiation (LTP). Using direct measurements of LTP in acute hippocampal slices and an in vitro LTP model of stimulated AMPAR exocytosis, we demonstrate that the Q-SNARE proteins syntaxin-3 and SNAP-47 are required for regulated AMPAR exocytosis during LTP but not for constitutive basal AMPAR exocytosis. In contrast, the R-SNARE protein synaptobrevin-2/VAMP2 contributes to both regulated and constitutive AMPAR exocytosis. Both the central complexin-binding and the N-terminal Munc18-binding sites of syntaxin-3 are essential for its postsynaptic role in LTP. Thus, postsynaptic exocytosis of AMPARs during LTP is mediated by a unique fusion machinery that is distinct from that used during presynaptic neurotransmitter release.

    View details for DOI 10.1016/j.neuron.2012.11.029

    View details for Web of Science ID 000317030800015

    View details for PubMedID 23395379

  • Input-specific control of reward and aversion in the ventral tegmental area NATURE Lammel, S., Lim, B. K., Ran, C., Huang, K. W., Betley, M. J., Tye, K. M., Deisseroth, K., Malenka, R. C. 2012; 491 (7423): 212-?

    Abstract

    Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (?-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

    View details for DOI 10.1038/nature11527

    View details for Web of Science ID 000310774300035

    View details for PubMedID 23064228

  • Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens NATURE Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., Malenka, R. C. 2012; 487 (7406): 183-U64

    Abstract

    Chronic stress is a strong diathesis for depression in humans and is used to generate animal models of depression. It commonly leads to several major symptoms of depression, including dysregulated feeding behaviour, anhedonia and behavioural despair. Although hypotheses defining the neural pathophysiology of depression have been proposed, the critical synaptic adaptations in key brain circuits that mediate stress-induced depressive symptoms remain poorly understood. Here we show that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin 4 receptor. Stress-elicited increases in behavioural measurements of anhedonia, but not increases in measurements of behavioural despair, are prevented by blocking these melanocortin 4 receptor-mediated synaptic changes in vivo. These results establish that stress-elicited anhedonia requires a neuropeptide-triggered, cell-type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.

    View details for DOI 10.1038/nature11160

    View details for Web of Science ID 000306278900029

    View details for PubMedID 22785313

  • Integrating synaptic plasticity and striatal circuit function in addiction CURRENT OPINION IN NEUROBIOLOGY Grueter, B. A., Rothwell, P. E., Malenka, R. C. 2012; 22 (3): 545-551

    Abstract

    Exposure to addictive drugs causes changes in synaptic function within the striatal complex, which can either mimic or interfere with the induction of synaptic plasticity. These synaptic adaptations include changes in the nucleus accumbens (NAc), a ventral striatal subregion important for drug reward and reinforcement, as well as the dorsal striatum, which may promote habitual drug use. As the behavioral effects of drugs of abuse are long-lasting, identifying persistent changes in striatal circuits induced by in vivo drug experience is of considerable importance. Within the striatum, drugs of abuse have been shown to induce modifications in dendritic morphology, ionotropic glutamate receptors (iGluR) and the induction of synaptic plasticity. Understanding the detailed molecular mechanisms underlying these changes in striatal circuit function will provide insight into how drugs of abuse usurp normal learning mechanisms to produce pathological behavior.

    View details for DOI 10.1016/j.conb.2011.09.009

    View details for Web of Science ID 000306634700024

    View details for PubMedID 22000687

  • Distinct Neuronal Coding Schemes in Memory Revealed by Selective Erasure of Fast Synchronous Synaptic Transmission NEURON Xu, W., Morishita, W., Buckmaster, P. S., Pang, Z. P., Malenka, R. C., Suedhof, T. C. 2012; 73 (5): 990-1001

    Abstract

    Neurons encode information by firing spikes in isolation or bursts and propagate information by spike-triggered neurotransmitter release that initiates synaptic transmission. Isolated spikes trigger neurotransmitter release unreliably but with high temporal precision. In contrast, bursts of spikes trigger neurotransmission reliably (i.e., boost transmission fidelity), but the resulting synaptic responses are temporally imprecise. However, the relative physiological importance of different spike-firing modes remains unclear. Here, we show that knockdown of synaptotagmin-1, the major Ca(2+) sensor for neurotransmitter release, abrogated neurotransmission evoked by isolated spikes but only delayed, without abolishing, neurotransmission evoked by bursts of spikes. Nevertheless, knockdown of synaptotagmin-1 in the hippocampal CA1 region did not impede acquisition of recent contextual fear memories, although it did impair the precision of such memories. In contrast, knockdown of synaptotagmin-1 in the prefrontal cortex impaired all remote fear memories. These results indicate that different brain circuits and types of memory employ distinct spike-coding schemes to encode and transmit information.

    View details for DOI 10.1016/j.neuron.2011.12.036

    View details for Web of Science ID 000301558600013

    View details for PubMedID 22405208

  • Postsynaptic Complexin Controls AMPA Receptor Exocytosis during LTP NEURON Ahmad, M., Polepalli, J. S., Goswami, D., Yang, X., Kaeser-Woo, Y. J., Suedhof, T. C., Malenka, R. C. 2012; 73 (2): 260-267

    Abstract

    Long-term potentiation (LTP) is a compelling synaptic correlate of learning and memory. LTP induction requires NMDA receptor (NMDAR) activation, which triggers SNARE-dependent exocytosis of AMPA receptors (AMPARs). However, the molecular mechanisms mediating AMPAR exocytosis induced by NMDAR activation remain largely unknown. Here, we show that complexin, a protein that regulates neurotransmitter release via binding to SNARE complexes, is essential for AMPAR exocytosis during LTP but not for the constitutive AMPAR exocytosis that maintains basal synaptic strength. The regulated postsynaptic AMPAR exocytosis during LTP requires binding of complexin to SNARE complexes. In hippocampal neurons, presynaptic complexin acts together with synaptotagmin-1 to mediate neurotransmitter release. However, postsynaptic synaptotagmin-1 is not required for complexin-dependent AMPAR exocytosis during LTP. These results suggest a complexin-dependent molecular mechanism for regulating AMPAR delivery to synapses, a mechanism that is surprisingly similar to presynaptic exocytosis but controlled by regulators other than synaptotagmin-1.

    View details for DOI 10.1016/j.neuron.2011.11.020

    View details for Web of Science ID 000299761600008

    View details for PubMedID 22284181

  • Comprehensive qPCR profiling of gene expression in single neuronal cells NATURE PROTOCOLS Citri, A., Pang, Z. P., Suedhof, T. C., Wernig, M., Malenka, R. C. 2012; 7 (1): 118-127

    Abstract

    A major challenge in neuronal stem cell biology lies in characterization of lineage-specific reprogrammed human neuronal cells, a process that necessitates the use of an assay sensitive to the single-cell level. Single-cell gene profiling can provide definitive evidence regarding the conversion of one cell type into another at a high level of resolution. The protocol we describe uses Fluidigm Biomark dynamic arrays for high-throughput expression profiling from single neuronal cells, assaying up to 96 independent samples with up to 96 quantitative PCR (qPCR) probes (equivalent to 9,216 reactions) in a single experiment, which can be completed within 2-3 d. The protocol enables simple and cost-effective profiling of several hundred transcripts from a single cell, and it could have numerous utilities.

    View details for DOI 10.1038/nprot.2011.430

    View details for Web of Science ID 000299108900011

    View details for PubMedID 22193304

  • The neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Soler-Llavina, G. J., Fuccillo, M. V., Ko, J., Suedhof, T. C., Malenka, R. C. 2011; 108 (40): 16502-16509

    Abstract

    Synaptic cell adhesion molecules, including the neurexin ligands, neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs), are thought to organize synapse assembly and specify synapse function. To test the synaptic role of these molecules in vivo, we performed lentivirally mediated knockdown of NL3, LRRTM1, and LRRTM2 in CA1 pyramidal cells of WT and NL1 KO mice at postnatal day (P)0 (when synapses are forming) and P21 (when synapses are largely mature). P0 knockdown of NL3 in WT or NL1 KO neurons did not affect excitatory synaptic transmission, whereas P0 knockdown of LRRTM1 and LRRTM2 selectively reduced AMPA receptor-mediated synaptic currents. P0 triple knockdown of NL3 and both LRRTMs in NL1 KO mice yielded greater reductions in AMPA and NMDA receptor-mediated currents, suggesting functional redundancy between NLs and LRRTMs during early synapse development. In contrast, P21 knockdown of LRRTMs did not alter excitatory transmission, whereas NL manipulations supported a role for NL1 in maintaining NMDA receptor-mediated transmission. These results show that neurexin ligands in vivo form a dynamic synaptic cell adhesion network, with compensation between NLs and LRRTMs during early synapse development and functional divergence upon synapse maturation.

    View details for DOI 10.1073/pnas.1114028108

    View details for Web of Science ID 000295536000012

    View details for PubMedID 21953696

  • Projection-Specific Modulation of Dopamine Neuron Synapses by Aversive and Rewarding Stimuli NEURON Lammel, S., Ion, D. I., Roeper, J., Malenka, R. C. 2011; 70 (5): 855-862

    Abstract

    Midbrain dopamine (DA) neurons are not homogeneous but differ in their molecular properties and responses to external stimuli. We examined whether the modulation of excitatory synapses on DA neurons by rewarding or aversive stimuli depends on the brain area to which these DA neurons project. We identified DA neuron subpopulations in slices after injection of "Retrobeads" into single target areas of adult mice and found differences in basal synaptic properties. Administration of cocaine selectively modified excitatory synapses on DA cells projecting to nucleus accumbens (NAc) medial shell while an aversive stimulus selectively modified synapses on DA cells projecting to medial prefrontal cortex. In contrast, synapses on DA neurons projecting to NAc lateral shell were modified by both rewarding and aversive stimuli, which presumably reflects saliency. These results suggest that the mesocorticolimbic DA system may be comprised of three anatomically distinct circuits, each modified by distinct aspects of motivationally relevant stimuli.

    View details for DOI 10.1016/j.neuron.2011.03.025

    View details for Web of Science ID 000291843500007

    View details for PubMedID 21658580

  • Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens NATURE NEUROSCIENCE Grueter, B. A., Brasnjo, G., Malenka, R. C. 2010; 13 (12): 1519-U107

    Abstract

    Synaptic modifications in the nucleus accumbens (NAc) are important for adaptive and pathological reward-dependent learning. Medium spiny neurons (MSNs), the major cell type in the NAc, participate in two parallel circuits that subserve distinct behavioral functions, yet little is known about differences in their electrophysiological and synaptic properties. Using bacterial artificial chromosome transgenic mice, we found that synaptic activation of group I metabotropic glutamate receptors in NAc MSNs in the indirect, but not direct, pathway led to the production of endocannabinoids, which activated presynaptic CB1 receptors to trigger endocannabinoid-mediated long-term depression (eCB-LTD) as well as postsynaptic transient receptor potential vanilloid 1 (TRPV1) channels to trigger a form of LTD resulting from endocytosis of AMPA receptors. These results reveal a previously unknown action of TRPV1 channels and indicate that the postsynaptic generation of endocannabinoids can modulate synaptic strength in a cell type-specific fashion by activating distinct pre- and postsynaptic targets.

    View details for DOI 10.1038/nn.2685

    View details for Web of Science ID 000284525800017

    View details for PubMedID 21076424

  • A calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression NATURE NEUROSCIENCE Jurado, S., Biou, V., Malenka, R. C. 2010; 13 (9): 1053-1055

    Abstract

    AKAP79/150 is a protein scaffold that is thought to position specific kinases (protein kinase A and C) and phosphatases (calcineurin) in appropriate synaptic domains so that their activities can regulate excitatory synaptic strength. Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin.

    View details for DOI 10.1038/nn.2613

    View details for Web of Science ID 000281332600008

    View details for PubMedID 20694001

  • Understanding Synapses: Past, Present, and Future NEURON Suedhof, T. C., Malenka, R. C. 2008; 60 (3): 469-476

    Abstract

    Classical physiological work by Katz, Eccles, and others revealed the central importance of synapses in brain function, and characterized the mechanisms involved in synaptic transmission. Building on this work, major advances in the past two decades have elucidated how synapses work molecularly. In the present perspective, we provide a short description of our personal view of these advances, suggest a series of important future questions about synapses, and discuss ideas about how best to achieve further progress in the field.

    View details for DOI 10.1016/j.neuron.2008.10.011

    View details for Web of Science ID 000260983800018

    View details for PubMedID 18995821

  • Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models NATURE Kreitzer, A. C., Malenka, R. C. 2007; 445 (7128): 643-647

    Abstract

    The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.

    View details for DOI 10.1038/nature05506

    View details for Web of Science ID 000244039400043

    View details for PubMedID 17287809

  • Synaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles. PLoS biology Bacaj, T., Wu, D., Burré, J., Malenka, R. C., Liu, X., Südhof, T. C. 2015; 13 (10)

    Abstract

    In forebrain neurons, Ca2+ triggers exocytosis of readily releasable vesicles by binding to synaptotagmin-1 and -7, thereby inducing fast and slow vesicle exocytosis, respectively. Loss-of-function of synaptotagmin-1 or -7 selectively impairs the fast and slow phase of release, respectively, but does not change the size of the readily-releasable pool (RRP) of vesicles as measured by stimulation of release with hypertonic sucrose, or alter the rate of vesicle priming into the RRP. Here we show, however, that simultaneous loss-of-function of both synaptotagmin-1 and -7 dramatically decreased the capacity of the RRP, again without altering the rate of vesicle priming into the RRP. Either synaptotagmin-1 or -7 was sufficient to rescue the RRP size in neurons lacking both synaptotagmin-1 and -7. Although maintenance of RRP size was Ca2+-independent, mutations in Ca2+-binding sequences of synaptotagmin-1 or synaptotagmin-7-which are contained in flexible top-loop sequences of their C2 domains-blocked the ability of these synaptotagmins to maintain the RRP size. Both synaptotagmins bound to SNARE complexes; SNARE complex binding was reduced by the top-loop mutations that impaired RRP maintenance. Thus, synaptotagmin-1 and -7 perform redundant functions in maintaining the capacity of the RRP in addition to nonredundant functions in the Ca2+ triggering of different phases of release.

    View details for DOI 10.1371/journal.pbio.1002267

    View details for PubMedID 26437117

  • Synaptotagmin-1 and-7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles PLOS BIOLOGY Bacaj, T., Wu, D., Burre, J., Malenka, R. C., Liu, X., Suedhof, T. C. 2015; 13 (10)
  • Viral-genetic tracing of the input-output organization of a central noradrenaline circuit. Nature Schwarz, L. A., Miyamichi, K., Gao, X. J., Beier, K. T., Weissbourd, B., DeLoach, K. E., Ren, J., Ibanes, S., Malenka, R. C., Kremer, E. J., Luo, L. 2015; 524 (7563): 88-92

    Abstract

    Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating. However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

    View details for DOI 10.1038/nature14600

    View details for PubMedID 26131933

  • Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits CELL Lerner, T. N., Shilyansky, C., Davidson, T. J., Evans, K. E., Beier, K. T., Zalocusky, K. A., Crow, A. K., Malenka, R. C., Luo, L., Tomer, R., Deisseroth, K. 2015; 162 (3): 635-647
  • ß-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling. Cell Anderson, G. R., Aoto, J., Tabuchi, K., Földy, C., Covy, J., Yee, A. X., Wu, D., Lee, S., Chen, L., Malenka, R. C., Südhof, T. C. 2015; 162 (3): 593-606

    Abstract

    ?- and ?-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that, although ?-neurexins are expressed at much lower levels than ?-neurexins, conditional knockout of ?-neurexins with continued expression of ?-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The ?-neurexin knockout phenotype was attenuated by CB1-receptor inhibition, which blocks presynaptic endocannabinoid signaling, or by 2-arachidonoylglycerol synthesis inhibition, which impairs postsynaptic endocannabinoid release. In synapses formed by CA1-region pyramidal neurons onto burst-firing subiculum neurons, presynaptic in vivo knockout of ?-neurexins aggravated endocannabinoid-mediated inhibition of synaptic transmission and blocked LTP; presynaptic CB1-receptor antagonists or postsynaptic 2-arachidonoylglycerol synthesis inhibition again reversed this block. Moreover, conditional knockout of ?-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic ?-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for ?-neurexins in the endocannabinoid-dependent regulation of neural circuits.

    View details for DOI 10.1016/j.cell.2015.06.056

    View details for PubMedID 26213384

  • beta-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling CELL Anderson, G. R., Aoto, J., Tabuchi, K., Foeldy, C., Covy, J., Yee, A. X., Wu, D., Lee, S., Chen, L., Malenka, R. C., Suedhof, T. C. 2015; 162 (3): 593-606
  • Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits. Cell Lerner, T. N., Shilyansky, C., Davidson, T. J., Evans, K. E., Beier, K. T., Zalocusky, K. A., Crow, A. K., Malenka, R. C., Luo, L., Tomer, R., Deisseroth, K. 2015; 162 (3): 635-647

    Abstract

    Recent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance--and the challenges--of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc). We identify two parallel nigrostriatal dopamine neuron subpopulations differing in biophysical properties, input wiring, output wiring to dorsomedial striatum (DMS) versus dorsolateral striatum (DLS), and natural activity patterns during free behavior. Our results reveal independently operating nigrostriatal information streams, with implications for understanding the logic of dopaminergic feedback circuits and the diversity of mammalian neuronal cell types.

    View details for DOI 10.1016/j.cell.2015.07.014

    View details for PubMedID 26232229

  • Single-Cell mRNA Profiling Reveals Cell-Type-Specific Expression of Neurexin Isoforms NEURON Fuccillo, M. V., Foeldy, C., Goekce, O., Rothwell, P. E., Sun, G. L., Malenka, R. C., Suedhof, T. C. 2015; 87 (2): 326-340

    Abstract

    Neurexins are considered central organizers of synapse architecture that are implicated in neuropsychiatric disorders. Expression of neurexins in hundreds of alternatively spliced isoforms suggested that individual neurons might exhibit a cell-type-specific neurexin expression pattern (a neurexin code). To test this hypothesis, we quantified the single-cell levels of neurexin isoforms and other trans-synaptic cell-adhesion molecules by microfluidics-based RT-PCR. We show that the neurexin repertoire displays pronounced cell-type specificity that is remarkably consistent within each type of neuron. Furthermore, we uncovered region-specific regulation of neurexin transcription and splice-site usage. Finally, we demonstrate that the transcriptional profiles of neurexins can be altered in an experience-dependent fashion by exposure to a drug of abuse. Our data provide evidence of cell-type-specific expression patterns of multiple neurexins at the single-cell level and suggest that expression of synaptic cell-adhesion molecules overlaps with other key features of cellular identity and diversity.

    View details for DOI 10.1016/j.neuron.2015.06.028

    View details for Web of Science ID 000361144200009

    View details for PubMedID 26182417

  • Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nature neuroscience Christoffel, D. J., Golden, S. A., Walsh, J. J., Guise, K. G., Heshmati, M., Friedman, A. K., Dey, A., Smith, M., Rebusi, N., Pfau, M., Ables, J. L., Aleyasin, H., Khibnik, L. A., Hodes, G. E., Ben-Dor, G. A., Deisseroth, K., Shapiro, M. L., Malenka, R. C., Ibanez-Tallon, I., Han, M., Russo, S. J. 2015; 18 (7): 962-964

    Abstract

    Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.

    View details for DOI 10.1038/nn.4034

    View details for PubMedID 26030846

  • Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress NATURE NEUROSCIENCE Christoffel, D. J., Golden, S. A., Walsh, J. J., Guise, K. G., Heshmati, M., Friedman, A. K., Dey, A., Smith, M., Rebusi, N., Pfau, M., Ables, J. L., Aleyasin, H., Khibnik, L. A., Hodes, G. E., Ben-Dor, G. A., Deisseroth, K., Shapiro, M. L., Malenka, R. C., Ibanez-Tallon, I., Han, M., Russo, S. J. 2015; 18 (7): 962-?

    View details for DOI 10.1038/nn.4034

    View details for Web of Science ID 000356866200011

  • Synaptic Function of Rab11Fip5: Selective Requirement for Hippocampal Long-Term Depression JOURNAL OF NEUROSCIENCE Bacaj, T., Ahmad, M., Jurado, S., Malenka, R. C., Suedhof, T. C. 2015; 35 (19): 7460-7474

    Abstract

    Postsynaptic AMPA-type glutamate receptors (AMPARs) are among the major determinants of synaptic strength and can be trafficked into and out of synapses. Neuronal activity regulates AMPAR trafficking during synaptic plasticity to induce long-term changes in synaptic strength, including long-term potentiation (LTP) and long-term depression (LTD). Rab family GTPases regulate most membrane trafficking in eukaryotic cells; particularly, Rab11 and its effectors are implicated in mediating postsynaptic AMPAR insertion during LTP. To explore the synaptic function of Rab11Fip5, a neuronal Rab11 effector and a candidate autism-spectrum disorder gene, we performed shRNA-mediated knock-down and genetic knock-out (KO) studies. Surprisingly, we observed robust shRNA-induced synaptic phenotypes that were rescued by a Rab11Fip5 cDNA but that were nevertheless not observed in conditional KO neurons. Both in cultured neurons and acute slices, KO of Rab11Fip5 had no significant effect on basic parameters of synaptic transmission, indicating that Rab11Fip5 is not required for fundamental synaptic operations, such as neurotransmitter release or postsynaptic AMPAR insertion. KO of Rab11Fip5 did, however, abolish hippocampal LTD as measured both in acute slices or using a chemical LTD protocol in cultured neurons but did not affect hippocampal LTP. The Rab11Fip5 KO mice performed normally in several behavioral tasks, including fear conditioning, but showed enhanced contextual fear extinction. These are the first findings to suggest a requirement for Rab11Fip5, and presumably Rab11, during LTD.

    View details for DOI 10.1523/JNEUROSCI.1581-14.2015

    View details for Web of Science ID 000356668800013

    View details for PubMedID 25972173

  • Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion CELL Venkatesh, H. S., Johung, T. B., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E. M., Mount, C. W., Polepalli, J., Mitra, S. S., Woo, P. J., Malenka, R. C., Vogel, H., Bredel, M., Mallick, P., Monje, M. 2015; 161 (4): 803-816

    Abstract

    Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

    View details for DOI 10.1016/j.cell.2015.04.012

    View details for Web of Science ID 000354175200014

  • Retinoic Acid and LTP Recruit Postsynaptic AMPA Receptors Using Distinct SNARE-Dependent Mechanisms NEURON Arendt, K. L., Zhang, Y., Jurado, S., Malenka, R. C., Suedhof, T. C., Chen, L. 2015; 86 (2): 442-456

    Abstract

    Retinoic acid (RA)-dependent homeostatic plasticity and NMDA receptor-dependent long-term potentiation (LTP), a form of Hebbian plasticity, both enhance synaptic strength by increasing the abundance of postsynaptic AMPA receptors (AMPARs). However, it is unclear whether the molecular mechanisms mediating AMPAR trafficking during homeostatic and Hebbian plasticity differ, and it is unknown how RA signaling impacts Hebbian plasticity. Here, we show that RA increases postsynaptic AMPAR abundance using an activity-dependent mechanism that requires a unique SNARE (soluble NSF-attachment protein receptor)-dependent fusion machinery different from that mediating LTP. Specifically, RA-induced AMPAR trafficking did not involve complexin, which activates SNARE complexes containing syntaxin-1 or -3, but not complexes containing syntaxin-4, whereas LTP required complexin. Moreover, RA-induced AMPAR trafficking utilized the Q-SNARE syntaxin-4, whereas LTP utilized syntaxin-3; both additionally required the Q-SNARE SNAP-47 and the R-SNARE synatobrevin-2. Finally, acute RA treatment blocked subsequent LTP expression, probably by increasing AMPAR trafficking. Thus, RA-induced homeostatic plasticity involves a novel, activity-dependent postsynaptic AMPAR-trafficking pathway mediated by a unique SNARE-dependent fusion machinery.

    View details for DOI 10.1016/j.neuron.2015.03.009

    View details for Web of Science ID 000353410000013

    View details for PubMedID 25843403

  • B-Lymphocyte-Mediated Delayed Cognitive Impairment following Stroke JOURNAL OF NEUROSCIENCE Doyle, K. P., Quach, L. N., Sole, M., Axtell, R. C., Nguyen, T. V., Soler-Llavina, G. J., Jurado, S., Han, J., Steinman, L., Longo, F. M., Schneider, J. A., Malenka, R. C., Buckwalter, M. S. 2015; 35 (5): 2133-2145

    Abstract

    Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.

    View details for DOI 10.1523/JNEUROSCI.4098-14.2015

    View details for Web of Science ID 000349671100027

    View details for PubMedID 25653369

  • Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons. Neuron Lammel, S., Steinberg, E. E., Földy, C., Wall, N. R., Beier, K., Luo, L., Malenka, R. C. 2015; 85 (2): 429-438

    Abstract

    Ventral tegmental area (VTA) dopamine (DA) neurons have been implicated in reward, aversion, salience, cognition, and several neuropsychiatric disorders. Optogenetic approaches involving transgenic Cre-driver mouse lines provide powerful tools for dissecting DA-specific functions. However, the emerging complexity of VTA circuits requires Cre-driver mouse lines that restrict transgene expression to a precisely defined cell population. Because of recent work reporting that VTA DA neurons projecting to the lateral habenula release GABA, but not DA, we performed an extensive anatomical, molecular, and functional characterization of prominent DA transgenic mouse driver lines. We find that transgenes under control of the tyrosine hydroxylase, but not the dopamine transporter, promoter exhibit dramatic non-DA cell-specific expression patterns within and around VTA nuclei. Our results demonstrate how Cre expression in unintentionally targeted cells in transgenic mouse lines can confound the interpretation of supposedly cell-type-specific experiments. This Matters Arising paper is in response to Stamatakis et al. (2013), published in Neuron. See also the Matters Arising Response paper by Stuber et al. (2015), published concurrently with this Matters Arising in Neuron.

    View details for DOI 10.1016/j.neuron.2014.12.036

    View details for PubMedID 25611513

  • Diversity of Transgenic Mouse Models for Selective Targeting of Midbrain Dopamine Neurons NEURON Lammel, S., Steinberg, E. E., Foeldy, C., Wall, N. R., Beier, K., Luo, L., Malenka, R. C. 2015; 85 (2): 429-438
  • The emerging role of nucleus accumbens oxytocin in social cognition. Biological psychiatry Dölen, G., Malenka, R. C. 2014; 76 (5): 354-355

    View details for DOI 10.1016/j.biopsych.2014.06.009

    View details for PubMedID 25103539

  • Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons. Brain Dragicevic, E., Poetschke, C., Duda, J., Schlaudraff, F., Lammel, S., Schiemann, J., Fauler, M., Hetzel, A., Watanabe, M., Lujan, R., Malenka, R. C., Striessnig, J., Liss, B. 2014; 137: 2287-2302

    Abstract

    Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca(2+) channels both contribute to Parkinson's disease pathology. L-type Ca(2+) channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson's disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca(2+) channel activity, internal Ca(2+), and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca(2+) channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca(2+) channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson's disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca(2+) channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson's disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.

    View details for DOI 10.1093/brain/awu131

    View details for PubMedID 24934288

  • Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors CELL Rothwell, P. E., Fuccillo, M. V., Maxeiner, S., Hayton, S. J., Gokce, O., Lim, B. K., Fowler, S. C., Malenka, R. C., Suedhof, T. C. 2014; 158 (1): 198-212

    Abstract

    In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology. PAPERFLICK:

    View details for DOI 10.1016/j.cell.2014.04.045

    View details for Web of Science ID 000340943100018

    View details for PubMedID 24995986

  • Natural Neural Projection Dynamics Underlying Social Behavior CELL Gunaydin, L. A., Grosenick, L., Finkelstein, J. C., Kauvar, I. V., Fenno, L. E., Adhikari, A., Lammel, S., Mirzabekov, J. J., Airan, R. D., Zalocusky, K. A., Tye, K. M., Anikeeva, P., Malenka, R. C., Deisseroth, K. 2014; 157 (7): 1535-1551

    Abstract

    Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.

    View details for DOI 10.1016/j.cell.2014.05.017

    View details for Web of Science ID 000340941900010

  • Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome CELL REPORTS Portmann, T., Yang, M., Mao, R., Panagiotakos, G., Ellegood, J., Dolen, G., Bader, P. L., Grueter, B. A., Goold, C., Fisher, E., Clifford, K., Rengarajan, P., Kalikhman, D., Loureiro, D., Saw, N. L., Zhou Zhengqui, Z. Q., Miller, M. A., Lerch, J. P., Henkelman, R. M., Shamloo, M., Malenka, R. C., Crawley, J. N., Dolmetsch, R. E. 2014; 7 (4): 1077-1092

    Abstract

    A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

    View details for DOI 10.1016/j.celrep.2014.03.036

    View details for Web of Science ID 000336495700018

  • Ionotropic NMDA Receptor Signaling Is Required for the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region JOURNAL OF NEUROSCIENCE Babiec, W. E., Guglietta, R., Jami, S. A., Morishita, W., Malenka, R. C., O'Dell, T. J. 2014; 34 (15): 5285-5290

    Abstract

    Previous studies have provided strong support for the notion that NMDAR-mediated increases in postsynaptic Ca(2+) have a crucial role in the induction of long-term depression (LTD). This view has recently been challenged, however, by findings suggesting that LTD induction is instead attributable to an ion channel-independent, metabotropic form of NMDAR signaling. Thus, to explore the role of ionotropic versus metabotropic NMDAR signaling in LTD, we examined the effects of varying extracellular Ca(2+) levels or blocking NMDAR channel ion fluxes with MK-801 on LTD and NMDAR signaling in the mouse hippocampal CA1 region. We find that the induction of LTD in the adult hippocampus is highly sensitive to extracellular Ca(2+) levels and that MK-801 blocks NMDAR-dependent LTD in the hippocampus of both adult and immature mice. Moreover, MK-801 inhibits NMDAR-mediated activation of p38-MAPK and dephosphorylation of AMPAR GluA1 subunits at sites implicated in LTD. Thus, our results indicate that the induction of LTD in the hippocampal CA1 region is dependent on ionotropic, rather than metabotropic, NMDAR signaling.

    View details for DOI 10.1523/JNEUROSCI.5419-13.2014

    View details for Web of Science ID 000334347700021

    View details for PubMedID 24719106

  • Reward and aversion in a heterogeneous midbrain dopamine system NEUROPHARMACOLOGY Lammel, S., Lim, B. K., Malenka, R. C. 2014; 76: 351-359

    Abstract

    The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

    View details for DOI 10.1016/j.neuropharm.2013.03.019

    View details for Web of Science ID 000330083600016

    View details for PubMedID 23578393

  • Synaptotagmin-1 and Synaptotagmin-7 Trigger Synchronous and Asynchronous Phases of Neurotransmitter Release NEURON Bacaj, T., Wu, D., Yang, X., Morishita, W., Zhou, P., Xu, W., Malenka, R. C., Suedhof, T. C. 2013; 80 (4): 947-959

    Abstract

    In forebrain neurons, knockout of synaptotagmin-1 blocks fast Ca(2+)-triggered synchronous neurotransmitter release but enables manifestation of slow Ca(2+)-triggered asynchronous release. Here, we show using single-cell PCR that individual hippocampal neurons abundantly coexpress two Ca(2+)-binding synaptotagmin isoforms, synaptotagmin-1 and synaptotagmin-7. In synaptotagmin-1-deficient synapses of excitatory and inhibitory neurons, loss of function of synaptotagmin-7 suppressed asynchronous release. This phenotype was rescued by wild-type but not mutant synaptotagmin-7 lacking functional Ca(2+)-binding sites. Even in synaptotagmin-1-containing neurons, synaptotagmin-7 ablation partly impaired asynchronous release induced by extended high-frequency stimulus trains. Synaptotagmins bind Ca(2+) via two C2 domains, the C2A and C2B domains. Surprisingly, synaptotagmin-7 function selectively required its C2A domain Ca(2+)-binding sites, whereas synaptotagmin-1 function required its C2B domain Ca(2+)-binding sites. Our data show that nearly all Ca(2+)-triggered release at a synapse is due to synaptotagmins, with synaptotagmin-7 mediating a slower form of Ca(2+)-triggered release that is normally occluded by faster synaptotagmin-1-induced release but becomes manifest upon synaptotagmin-1 deletion.

    View details for DOI 10.1016/j.neuron.2013.10.026

    View details for Web of Science ID 000327281200012

  • Presynaptic Neurexin-3 Alternative Splicing trans-Synaptically Controls Postsynaptic AMPA Receptor Trafficking CELL Aoto, J., Martinelli, D. C., Malenka, R. C., Tabuchi, K., Suedhof, T. C. 2013; 154 (1): 75-88

    Abstract

    Neurexins are essential presynaptic cell adhesion molecules that are linked to schizophrenia and autism and are subject to extensive alternative splicing. Here, we used a genetic approach to test the physiological significance of neurexin alternative splicing. We generated knockin mice in which alternatively spliced sequence #4 (SS4) of neuexin-3 is constitutively included but can be selectively excised by cre-recombination. SS4 of neurexin-3 was chosen because it is highly regulated and controls neurexin binding to neuroligins, LRRTMs, and other ligands. Unexpectedly, constitutive inclusion of SS4 in presynaptic neurexin-3 decreased postsynaptic AMPA, but not NMDA receptor levels, and enhanced postsynaptic AMPA receptor endocytosis. Moreover, constitutive inclusion of SS4 in presynaptic neurexin-3 abrogated postsynaptic AMPA receptor recruitment during NMDA receptor-dependent LTP. These phenotypes were fully rescued by constitutive excision of SS4 in neurexin-3. Thus, alternative splicing of presynaptic neurexin-3 controls postsynaptic AMPA receptor trafficking, revealing an unanticipated alternative splicing mechanism for trans-synaptic regulation of synaptic strength and long-term plasticity.

    View details for DOI 10.1016/j.cell.2013.05.060

    View details for Web of Science ID 000321327900011

    View details for PubMedID 23827676

  • Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Xu, P., Grueter, B. A., Britt, J. K., McDaniel, L., Huntington, P. J., Hodge, R., Tran, S., Mason, B. L., Lee, C., Linh Vong, L., Lowell, B. B., Malenka, R. C., Lutter, M., Pieper, A. A. 2013; 110 (26): 10759-10764
  • Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron Földy, C., Malenka, R. C., Südhof, T. C. 2013; 78 (3): 498-509

    Abstract

    Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects produced by the neuroligin-3 R451C-knockin but not the neuroligin-3 knockout mutation, both mutations dramatically impaired tonic but not phasic endocannabinoid signaling. Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology.

    View details for DOI 10.1016/j.neuron.2013.02.036

    View details for PubMedID 23583622

  • Delta FosB differentially modulates nucleus accumbens direct and indirect pathway function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Grueter, B. A., Robison, A. J., Neve, R. L., Nestler, E. J., Malenka, R. C. 2013; 110 (5): 1923-1928

    Abstract

    Synaptic modifications in nucleus accumbens (NAc) medium spiny neurons (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modification of NAc MSN synapses may occur in part via changes in the transcriptional potential of certain genes in a cell type?specific manner. The transcription factor ?FosB is one of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. Here, we demonstrate that overexpression of ?FosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor?expressing direct pathway MSNs in both the NAc shell and core. In contrast, ?FosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor?expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that ?FosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. To determine the behavioral consequences of cell type-specific actions of ?FosB, we selectively overexpressed ?FosB in D1 direct or D2 indirect MSNs in NAc in vivo and found that direct (but not indirect) pathway MSN expression enhances behavioral responses to cocaine. These results reveal that ?FosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.

    View details for DOI 10.1073/pnas.1221742110

    View details for Web of Science ID 000314558100069

    View details for PubMedID 23319622

  • Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Anderson, G. R., Galfin, T., Xu, W., Aoto, J., Malenka, R. C., Suedhof, T. C. 2012; 109 (44): 18120-18125

    Abstract

    Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.

    View details for DOI 10.1073/pnas.1216398109

    View details for Web of Science ID 000311149900087

    View details for PubMedID 23074245

  • Dopaminergic Neurons from Midbrain-Specified Human Embryonic Stem Cell-Derived Neural Stem Cells Engrafted in a Monkey Model of Parkinson's Disease PLOS ONE Daadi, M. M., Grueter, B. A., Malenka, R. C., Redmond, D. E., Steinberg, G. K. 2012; 7 (7)

    Abstract

    The use of human embryonic stem cells (hESCs) to repair diseased or injured brain is promising technology with significant humanitarian, societal and economic impact. Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. The generation of this cell type will fulfill a currently unmet therapeutic need. We report on the isolation and perpetuation of a midbrain-specified self-renewable human neural stem cell line (hNSCs) from hESCs. These hNSCs grew as a monolayer and uniformly expressed the neural precursor markers nestin, vimentin and a radial glial phenotype. We describe a process to direct the differentiation of these hNSCs towards the DA lineage. Glial conditioned media acted synergistically with fibroblastic growth factor and leukemia inhibitory factor to induce the expression of the DA marker, tyrosine hydroxylase (TH), in the hNSC progeny. The glial-derived neurotrophic factor did not fully mimic the effects of conditioned media. The hNSCs expressed the midbrain-specific transcription factors Nurr1 and Pitx3. The inductive effects did not modify the level of the glutamic acid decarboxylase (GAD) transcript, a marker for GABAergic neurons, while the TH transcript increased 10-fold. Immunocytochemical analysis demonstrated that the TH-expressing cells did not co-localize with GAD. The transplantation of these DA-induced hNSCs into the non-human primate MPTP model of PD demonstrated that the cells maintain their DA-induced phenotype, extend neurite outgrowths and express synaptic markers.

    View details for Web of Science ID 000306507000069

    View details for PubMedID 22815935

  • A Comparison of Striatal-Dependent Behaviors in Wild-Type and Hemizygous Drd1a and Drd2 BAC Transgenic Mice JOURNAL OF NEUROSCIENCE Nelson, A. B., Hang, G. B., Grueter, B. A., Pascoli, V., Luscher, C., Malenka, R. C., Kreitzer, A. C. 2012; 32 (27): 9119-9123

    Abstract

    Studies of striatal physiology and motor control have increasingly relied on the use of bacterial artificial chromosome (BAC) transgenic mice expressing fluorophores or other genes under the control of genetic regulatory elements for the dopamine D1 receptor (D1R) or dopamine D2 receptor (D2R). Three recent studies have compared wild-type, D1R, and D2R BAC transgenic mice, and found significant differences in physiology and behavior, calling into question the use of these mice in studies of normal circuit function. We repeated the behavioral portions of these studies in wild-type C57BL/6 mice and hemizygous Drd1a-td Tomato (D1-Tmt), Drd1a-eGFP (D1-GFP), and Drd2-eGFP (D2-GFP) mice backcrossed into the C57BL/6 background. Our three laboratories independently found that open-field locomotion, acute locomotor responses to cocaine (20 mg/kg), locomotor sensitization to 5 d of daily injections of cocaine (15 mg/kg) or amphetamine (3 mg/kg), cocaine (20 mg/kg) conditioned place preference, and active avoidance learning to paired light and footshock were indistinguishable in these four mouse lines. These results suggest that while it is crucial to screen new transgenic mouse lines for abnormal behavior and physiology, these BAC transgenic mouse lines remain extremely valuable tools for evaluating the cellular, synaptic, and circuit basis of striatal motor control and associative learning.

    View details for DOI 10.1523/JNEUROSCI.0224-12.2012

    View details for Web of Science ID 000306193900002

    View details for PubMedID 22764221

  • NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD) COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY Luescher, C., Malenka, R. C. 2012; 4 (6)

    Abstract

    Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory.

    View details for DOI 10.1101/cshperspect.a005710

    View details for Web of Science ID 000308028500002

    View details for PubMedID 22510460

  • Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Etherton, M., Foeldy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M., Malenka, R. C., Suedhof, T. C. 2011; 108 (33): 13764-13769

    Abstract

    Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ?1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.

    View details for DOI 10.1073/pnas.1111093108

    View details for Web of Science ID 000293895100079

    View details for PubMedID 21808020

  • Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons JOURNAL OF CELL BIOLOGY Ko, J., Soler-Llavina, G. J., Fuccillo, M. V., Malenka, R. C., Suedhof, T. C. 2011; 194 (2): 323-334

    Abstract

    Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid-mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ?40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca(2+) influx or Ca(2+)/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca(2+)/CaM-dependent signaling pathway.

    View details for DOI 10.1083/jcb.201101072

    View details for Web of Science ID 000293121700014

    View details for PubMedID 21788371

  • Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling NEURON Luescher, C., Malenka, R. C. 2011; 69 (4): 650-663
  • Calcium Binding to PICK1 Is Essential for the Intracellular Retention of AMPA Receptors Underlying Long-Term Depression JOURNAL OF NEUROSCIENCE Citri, A., Bhattacharyya, S., Ma, C., Morishita, W., Fang, S., Rizo, J., Malenka, R. C. 2010; 30 (49): 16437-16452

    Abstract

    NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the hippocampus is mediated primarily by the calcium-dependent removal of AMPA receptors (AMPARs) from the postsynaptic density. The AMPAR-binding, PDZ (PSD-95/Dlg/ZO1) and BAR (Bin/amphiphysin/Rvs) domain-containing protein PICK1 has been implicated in the regulation of AMPAR trafficking underlying several forms of synaptic plasticity. Using a strategy involving small hairpin RNA-mediated knockdown of PICK1 and its replacement with recombinant PICK1, we performed a detailed structure-function analysis of the role of PICK1 in hippocampal synaptic plasticity and the underlying NMDAR-induced AMPAR trafficking. We found that PICK1 is not necessary for maintenance of the basal synaptic complement of AMPARs or expression of either metabotropic glutamate receptor-dependent LTD or NMDAR-dependent LTP. Rather, PICK1 function is specific to NMDAR-dependent LTD and the underlying AMPAR trafficking. Furthermore, although PICK1 does not regulate the initial phase of NMDAR-induced AMPAR endocytosis, it is required for intracellular retention of internalized AMPARs. Detailed biophysical analysis of an N-terminal acidic motif indicated that it is involved in intramolecular electrostatic interactions that are disrupted by calcium. Mutations that interfered with the calcium-induced structural changes in PICK1 precluded LTD and the underlying NMDAR-induced intracellular retention of AMPARs. These findings support a model whereby calcium-induced modification of PICK1 structure is critical for its function in the retention of internalized AMPARs that underlies the expression of hippocampal NMDAR-dependent LTD.

    View details for DOI 10.1523/JNEUROSCI.4478-10.2010

    View details for Web of Science ID 000285089100005

    View details for PubMedID 21147983

  • The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens TRENDS IN NEUROSCIENCES Russo, S. J., Dietz, D. M., Dumitriu, D., Morrison, J. H., Malenka, R. C., Nestler, E. J. 2010; 33 (6): 267-276

    Abstract

    Addictive drugs cause persistent restructuring of several neuronal cell types in the limbic regions of brain thought to be responsible for long-term behavioral plasticity driving addiction. Although these structural changes are well documented in nucleus accumbens medium spiny neurons, little is known regarding the underlying molecular mechanisms. Additionally, it remains unclear whether structural plasticity and its synaptic concomitants drive addictive behaviors or whether they reflect homeostatic compensations to the drug not related to addiction per se. Here, we discuss recent paradoxical data, which either support or oppose the hypothesis that drug-induced changes in dendritic spines drive addictive behavior. We define areas where future investigation can provide a more detailed picture of drug-induced synaptic reorganization, including ultrastructural, electrophysiological and behavioral studies.

    View details for DOI 10.1016/j.tins.2010.02.002

    View details for Web of Science ID 000279363800002

    View details for PubMedID 20207024

  • LRRTM2 Functions as a Neurexin Ligand in Promoting Excitatory Synapse Formation NEURON Ko, J., Fuccillo, M. V., Malenka, R. C., Suedhof, T. C. 2009; 64 (6): 791-798

    Abstract

    Recently, leucine-rich repeat transmembrane proteins (LRRTMs) were found to be synaptic cell-adhesion molecules that, when expressed in nonneuronal cells, induce presynaptic differentiation in contacting axons. We now demonstrate that LRRTM2 induces only excitatory synapses, and that it also acts to induce synapses in transfected neurons similarly to neuroligin-1. Using affinity chromatography, we identified alpha- and beta-neurexins as LRRTM2 ligands, again rendering LRRTM2 similar to neuroligin-1. However, whereas neuroligins bind neurexins containing or lacking an insert in splice site #4, LRRTM2 only binds neurexins lacking an insert in splice site #4. Binding of neurexins to LRRTM2 can produce cell-adhesion junctions, consistent with a trans-interaction regulated by neurexin alternative splicing, and recombinant neurexin-1beta blocks LRRTM2's ability to promote presynaptic differentiation. Thus, our data suggest that two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor, but that their binding is subject to distinct regulatory mechanisms.

    View details for DOI 10.1016/j.neuron.2009.12.012

    View details for Web of Science ID 000273425800007

    View details for PubMedID 20064387

  • N-methyl-d-aspartate receptor- and metabotropic glutamate receptor-dependent long-term depression are differentially regulated by the ubiquitin-proteasome system EUROPEAN JOURNAL OF NEUROSCIENCE Citri, A., Soler-Llavina, G., Bhattacharyya, S., Malenka, R. C. 2009; 30 (8): 1443-1450

    Abstract

    Long-term depression (LTD) in CA1 pyramidal neurons can be induced by activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs), both of which elicit changes in synaptic efficacy through alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) endocytosis. To address the role of the ubiquitin-proteasome system in regulating AMPAR endocytosis during these forms of LTD, we examined the effects of pharmacological inhibitors of proteasomal degradation and protein ubiquitination on endocytosis of glutamate receptor 1 (GluR1) -containing AMPARs in dissociated rat hippocampal cultures as well as LTD of excitatory synaptic responses in acute rat hippocampal slices. Our findings suggest that the contribution of the ubiquitin-proteasome system to NMDAR-induced vs. mGluR-induced AMPAR endocytosis and the consequent LTD differs significantly. NMDAR-induced AMPAR endocytosis and LTD occur independently of proteasome function but appear to depend, at least in part, on ubiquitination. In contrast, mGluR-induced AMPAR endocytosis and LTD are enhanced by inhibition of proteasomal degradation, as well as by the inhibitor of protein ubiquitination. Furthermore, the decay of mGluR-induced membrane depolarization and Erk activation is delayed following inhibition of either ubiquitination or proteasomal degradation. These results suggest that, although NMDAR-dependent LTD may utilize ubiquitin as a signal for AMPAR endocytosis, mGluR-induced signaling and LTD are limited by a feedback mechanism that involves the ubiquitin-proteasome system.

    View details for DOI 10.1111/j.1460-9568.2009.06950.x

    View details for Web of Science ID 000270958700001

    View details for PubMedID 19821836

  • Molecular and Magnetic Resonance Imaging of Human Embryonic Stem Cell-Derived Neural Stem Cell Grafts in Ischemic Rat Brain MOLECULAR THERAPY Daadi, M. M., Li, Z., Arac, A., Grueter, B. A., Sofilos, M., Malenka, R. C., Wu, J. C., Steinberg, G. K. 2009; 17 (7): 1282-1291

    Abstract

    Real-time imaging of transplanted stem cells is essential for understanding their interactions in vivo with host environments, for tracking cell fate and function and for successful delivery and safety monitoring in the clinical setting. In this study, we used bioluminescence (BLI) and magnetic resonance imaging (MRI) to visualize the fate of grafted human embryonic stem cell (hESC)-derived human neural stem cells (hNSCs) in stroke-damaged rat brain. The hNSCs were genetically engineered with a lentiviral vector carrying a double fusion (DF) reporter gene that stably expressed enhanced green fluorescence protein (eGFP) and firefly luciferase (fLuc) reporter genes. The hNSCs were self-renewable, multipotent, and expressed markers for neural stem cells. Cell survival was tracked noninvasively by MRI and BLI for 2 months after transplantation and confirmed histologically. Electrophysiological recording from grafted GFP(+) cells and immuno-electronmicroscopy demonstrated connectivity. Grafted hNSCs differentiated into neurons, into oligodendrocytes in stroke regions undergoing remyelination and into astrocytes extending processes toward stroke-damaged vasculatures. Our data suggest that the combination of BLI and MRI modalities provides reliable real-time monitoring of cell fate.

    View details for DOI 10.1038/mt.2009.104

    View details for Web of Science ID 000267785800021

    View details for PubMedID 19436269

  • A critical role for PSD-95/AKAP interactions in endocytosis of synaptic AMPA receptors NATURE NEUROSCIENCE Bhattacharyya, S., Biou, V., Xu, W., Schlueter, O., Malenka, R. C. 2009; 12 (2): 172-181

    Abstract

    The endocytosis of AMPA receptors (AMPARs) underlies several forms of synaptic plasticity, including NMDA receptor (NMDAR)-dependent long-term depression (LTD), but the molecular mechanisms responsible for this trafficking remain unknown. We found that PSD-95, a major postsynaptic density protein, is important for NMDAR-triggered endocytosis of synaptic AMPARs in rat neuron cultures because of its binding to A kinase-anchoring protein 150 (AKAP150), a scaffold for specific protein kinases and phosphatases. Knockdown of PSD-95 with shRNA blocked NMDAR-triggered, but not constitutive or mGluR-triggered, endocytosis of AMPARs. Deletion of PSD-95's Src homology 3 and guanylate kinase-like domains, as well as a point mutation (L460P), both of which inhibit binding of PSD-95 to AKAP150, also blocked NMDAR-triggered AMPAR endocytosis. Furthermore, expression of a mutant AKAP150 that does not bind calcineurin inhibited this NMDAR-triggered trafficking event. Our results suggest that PSD-95's interaction with AKAP150 is critical for NMDAR-triggered AMPAR endocytosis and LTD, possibly because these scaffolds position calcineurin in the appropriate subsynaptic domain.

    View details for DOI 10.1038/nn.2249

    View details for Web of Science ID 000263182000018

    View details for PubMedID 19169250

  • Coordinated Changes in Dendritic Arborization and Synaptic Strength during Neural Circuit Development NEURON Peng, Y., He, S., Marie, H., Zeng, S., Ma, J., Tan, Z., Lee, S. Y., Malenka, R. C., Yu, X. 2009; 61 (1): 71-84

    Abstract

    Neural circuit development requires concurrent morphological and functional changes. Here, we identify coordinated and inversely correlated changes in dendritic morphology and mEPSC amplitude following increased neural activity. We show that overexpression of beta-catenin, a molecule that increases total dendritic length, mimics the effects of increased neuronal activity by scaling down mEPSC amplitudes, while postsynaptic expression of a protein that sequesters beta-catenin reverses the effects of activity on reducing mEPSC amplitudes. These results were confirmed immunocytochemically as changes in the size and density of surface synaptic AMPA receptor clusters. In individual neurons there was an inverse linear relationship between total dendritic length and average mEPSC amplitude. Importantly, beta-catenin overexpression in vivo promoted dendritic growth and reduced mEPSC amplitudes. Together, these results demonstrate that coordinated changes in dendritic morphology and unitary excitatory synaptic strength may serve as an important intrinsic mechanism that helps prevent neurons from overexcitation during neural circuit development.

    View details for DOI 10.1016/j.neuron.2008.11.015

    View details for Web of Science ID 000262614400009

    View details for PubMedID 19146814

  • Functional Engraftment of the Medial Ganglionic Eminence Cells in Experimental Stroke Model CELL TRANSPLANTATION Daadi, M. M., Lee, S. H., Arac, A., Grueter, B. A., Bhatnagar, R., Maag, A., Schaar, B., Malenka, R. C., Palmer, T. D., Steinberg, G. K. 2009; 18 (7): 815-826

    Abstract

    Currently there are no effective treatments targeting residual anatomical and behavioral deficits resulting from stroke. Evidence suggests that cell transplantation therapy may enhance functional recovery after stroke through multiple mechanisms. We used a syngeneic model of neural transplantation to explore graft-host communications that enhance cellular engraftment.The medial ganglionic eminence (MGE) cells were derived from 15-day-old transgenic rat embryos carrying green fluorescent protein (GFP), a marker, to easily track the transplanted cells. Adult rats were subjected to transient intraluminal occlusion of the medial cerebral artery. Two weeks after stroke, the grafts were deposited into four sites, along the rostro-caudal axis and medially to the stroke in the penumbra zone. Control groups included vehicle and fibroblast transplants. Animals were subjected to motor behavioral tests at 4 week posttransplant survival time. Morphological analysis demonstrated that the grafted MGE cells differentiated into multiple neuronal subtypes, established synaptic contact with host cells, increased the expression of synaptic markers, and enhanced axonal reorganization in the injured area. Initial patch-clamp recording demonstrated that the MGE cells received postsynaptic currents from host cells. Behavioral analysis showed reduced motor deficits in the rotarod and elevated body swing tests. These findings suggest that graft-host interactions influence the fate of grafted neural precursors and that functional recovery could be mediated by neurotrophic support, new synaptic circuit elaboration, and enhancement of the stroke-induced neuroplasticity.

    View details for DOI 10.3727/096368909X470829

    View details for Web of Science ID 000271253200013

    View details for PubMedID 19500468

  • Destabilization of the Postsynaptic Density by PSD-95 Serine 73 Phosphorylation Inhibits Spine Growth and Synaptic Plasticity NEURON Steiner, P., Higley, M. J., Xu, W., Czervionke, B. L., Malenka, R. C., Sabatini, B. L. 2008; 60 (5): 788-802

    Abstract

    Long-term potentiation (LTP) is accompanied by dendritic spine growth and changes in the composition of the postsynaptic density (PSD). We find that activity-dependent growth of apical spines of CA1 pyramidal neurons is accompanied by destabilization of the PSD that results in transient loss and rapid replacement of PSD-95 and SHANK2. Signaling through PSD-95 is required for activity-dependent spine growth and trafficking of SHANK2. N-terminal PDZ and C-terminal guanylate kinase domains of PSD-95 are required for both processes, indicating that PSD-95 coordinates multiple signals to regulate morphological plasticity. Activity-dependent trafficking of PSD-95 is triggered by phosphorylation at serine 73, a conserved calcium/calmodulin-dependent protein kinase II (CaMKII) consensus phosphorylation site, which negatively regulates spine growth and potentiation of synaptic currents. We propose that PSD-95 and CaMKII act at multiple steps during plasticity induction to initially trigger and later terminate spine growth by trafficking growth-promoting PSD proteins out of the active spine.

    View details for DOI 10.1016/j.neuron.2008.10.014

    View details for Web of Science ID 000261746700011

    View details for PubMedID 19081375

  • Striatal Plasticity and Basal Ganglia Circuit Function NEURON Kreitzer, A. C., Malenka, R. C. 2008; 60 (4): 543-554

    Abstract

    The dorsal striatum, which consists of the caudate and putamen, is the gateway to the basal ganglia. It receives convergent excitatory afferents from cortex and thalamus and forms the origin of the direct and indirect pathways, which are distinct basal ganglia circuits involved in motor control. It is also a major site of activity-dependent synaptic plasticity. Striatal plasticity alters the transfer of information throughout basal ganglia circuits and may represent a key neural substrate for adaptive motor control and procedural memory. Here, we review current understanding of synaptic plasticity in the striatum and its role in the physiology and pathophysiology of basal ganglia function.

    View details for DOI 10.1016/j.neuron.2008.11.005

    View details for Web of Science ID 000261603200006

    View details for PubMedID 19038213

  • RiM1 alpha phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kaeser, P. S., Kwon, H., Blundell, J., Chevaleyre, V., Morishita, W., Malenka, R. C., Powell, C. M., Castillo, P. E., Sudhof, T. C. 2008; 105 (38): 14680-14685

    Abstract

    Activation of presynaptic cAMP-dependent protein kinase A (PKA) triggers presynaptic long-term plasticity in synapses such as cerebellar parallel fiber and hippocampal mossy fiber synapses. RIM1alpha, a large multidomain protein that forms a scaffold at the presynaptic active zone, is essential for presynaptic long-term plasticity in these synapses and is phosphorylated by PKA at serine-413. Previous studies suggested that phosphorylation of RIM1alpha at serine-413 is required for presynaptic long-term potentiation in parallel fiber synapses formed in vitro by cultured cerebellar neurons and that this type of presynaptic long-term potentiation is mediated by binding of 14-3-3 proteins to phosphorylated serine-413. To test the role of serine-413 phosphorylation in vivo, we have now produced knockin mice in which serine-413 is mutated to alanine. Surprisingly, we find that in these mutant mice, three different forms of presynaptic PKA-dependent long-term plasticity are normal. Furthermore, we observed that in contrast to RIM1alpha KO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1alpha is not due to compensation by RIM2alpha because mice carrying both the serine-413 substitution and a RIM2alpha deletion still exhibited normal long-term presynaptic plasticity. Thus, phosphorylation of serine-413 of RIM1alpha is not essential for PKA-dependent long-term presynaptic plasticity in vivo, suggesting that PKA operates by a different mechanism despite the dependence of long-term presynaptic plasticity on RIM1alpha.

    View details for DOI 10.1073/pnas.0806679105

    View details for Web of Science ID 000259592400081

    View details for PubMedID 18799741

  • Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area JOURNAL OF NEUROSCIENCE Argilli, E., Sibley, D. R., Malenka, R. C., England, P. M., Bonci, A. 2008; 28 (37): 9092-9100

    Abstract

    Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activity-dependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D(5) receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaine-induced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spike-timing-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro.

    View details for DOI 10.1523/JNEUROSCI.1001-08.2008

    View details for Web of Science ID 000259094800004

    View details for PubMedID 18784289

  • Spike timing-dependent long-term potentiation in ventral tegmental area dopamine cells requires PKC JOURNAL OF NEUROPHYSIOLOGY Luu, P., Malenka, R. C. 2008; 100 (1): 533-538

    Abstract

    Long-term potentiation (LTP) of excitatory synapses on ventral tegmental area (VTA) dopamine (DA) cells is thought to play an important role in mediating some of the behavioral effects of drugs of abuse yet little is known about its underlying mechanisms. We find that spike timing-dependent LTP (STD LTP) in VTA DA cells is absent in slices prepared from mice previously administered cocaine, suggesting that cocaine-induced LTP and STD LTP share underlying mechanisms. This form of STD LTP is dependent on NMDA receptor (NMDAR) activation and a rise in postsynaptic calcium but surprisingly was not affected by an inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII). It was blocked by antagonists of conventional isoforms of PKC, whereas activation of protein kinase C (PKC) using a phorbol ester enhanced synaptic strength. These results suggest that NMDAR-mediated activation of PKC, but not CaMKII, is a critical trigger for LTP in VTA DA cells.

    View details for DOI 10.1152/jn.01384.2007

    View details for Web of Science ID 000257635400048

    View details for PubMedID 18450581

  • Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex NEURON Kaneko, M., Stellwagen, D., Malenka, R. C., Stryker, M. P. 2008; 58 (5): 673-680

    Abstract

    Rapid, experience-dependent plasticity in developing visual cortex is thought to be competitive. After monocular visual deprivation, the reduction in response of binocular neurons to one eye is matched by a corresponding increase to the other. Chronic optical imaging in mice deficient in TNFalpha reveals the normal initial loss of deprived-eye responses, but the subsequent increase in response to the open eye is absent. This mutation also blocks homeostatic synaptic scaling of mEPSCs in visual cortex in vitro, without affecting LTP. In monocular cortex, thought not to be subject to competition, responses in TNFalpha mutants are as reduced as in the binocular zone. Pharmacological inhibition of endogenous TNFalpha in wild-type mice phenocopies the knockout. These findings suggest that experience-dependent competition in developing visual cortex is the outcome of two distinct, noncompetitive processes, a loss of deprived-eye responses followed by an apparently homeostatic increase in responses dependent on TNFalpha signaling.

    View details for DOI 10.1016/j.neuron.2008.04.023

    View details for Web of Science ID 000256870800006

    View details for PubMedID 18549780

  • Interactions between drebrin and Ras regulate dendritic spine plasticity EUROPEAN JOURNAL OF NEUROSCIENCE Biou, V., Brinkhaus, H., Malenka, R. C., Matus, A. 2008; 27 (11): 2847-2859

    Abstract

    Dendritic spines are major sites of morphological plasticity in the CNS, but the molecular mechanisms that regulate their dynamics remain poorly understood. Here we show that the association of drebrin with actin filaments plays a major role in regulating dendritic spine stability and plasticity. Overexpressing drebrin or the internal actin-binding site of drebrin in rat hippocampal neurons destabilized mature dendritic spines so that they lost synaptic contacts and came to resemble immature dendritic filopodia. Drebrin-induced spine destabilization was dependent on Ras activation: expression of constitutively active Ras destabilized spine morphology whereas drebrin-induced spine destabilization was rescued by co-expressing dominant negative Ras. Conversely, RNAi-mediated drebrin knockdown prevented Ras-induced destabilization and promoted spine maturation in developing neurons. Together these data demonstrate a novel mechanism in which the balance between stability and plasticity in dendritic spines depends on binding of drebrin to actin filaments in a manner that is regulated by Ras.

    View details for DOI 10.1111/j.1460-9568.2008.06269.x

    View details for Web of Science ID 000256717000006

    View details for PubMedID 18588530

  • CREB modulates the functional output of nucleus accumbens neurons - A critical role of N-methyl-D-aspartate glutamate receptor (NMDAR) receptors JOURNAL OF BIOLOGICAL CHEMISTRY Huang, Y. H., Lin, Y., Brown, T. E., Han, M., Saal, D. B., Neve, R. L., Zukin, R. S., Sorg, B. A., Nestler, E. J., Malenka, R. C., Dong, Y. 2008; 283 (5): 2751-2760

    Abstract

    Nucleus accumbens (NAc) medium spiny neurons cycle between two states, a functionally inactive downstate and a functionally active upstate. Here, we show that activation of the transcription factor cAMP-response element-binding protein (CREB), a common molecular response to several drugs of abuse, increases both duration of the upstate and action potential firing during the upstate. This effect of CREB is mediated by enhanced N-methyl-d-aspartate glutamate receptor (NMDAR) function: increased CREB activity increases both NMDAR-mediated synaptic currents and surface level of NMDARs, while inhibition of NMDARs abolishes the effect of CREB on upstate duration. Furthermore, mimicking the effect of CREB by pharmacological enhancement of NMDAR function in the NAc in vivo suppressed novelty- and cocaine-elicited locomotor activity. These findings suggest that by enhancing NMDAR-mediated synaptic transmission, CREB activation promotes the proportion of time NAc neurons spend in the upstate. This effect, along with the CREB enhancement of NAc membrane excitability (Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E. J., and Malenka, R. C. (2006) Nat. Neurosci. 9, 475-477), may counteract drug-induced maladaptations in the NAc and thus ameliorate the addictive state.

    View details for DOI 10.1074/jbc.M706578200

    View details for Web of Science ID 000252622300033

    View details for PubMedID 18055458

  • Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD NEURON Xu, W., Schlueter, O. M., Steiner, P., Czervionke, B. L., Sabatini, B., Malenka, R. C. 2008; 57 (2): 248-262

    Abstract

    The postsynaptic density protein PSD-95 influences synaptic AMPA receptor (AMPAR) content and may play a critical role in LTD. Here we demonstrate that the effects of PSD-95 on AMPAR-mediated synaptic responses and LTD can be dissociated. Our findings suggest that N-terminal-domain-mediated dimerization is important for PSD-95's effect on basal synaptic AMPAR function, whereas the C-terminal SH(3)-GK domains are also necessary for localizing PSD-95 to synapses. We identify PSD-95 point mutants (Q15A, E17R) that maintain PSD-95's influence on basal AMPAR synaptic responses yet block LTD. These point mutants increase the proteolysis of PSD-95 within its N-terminal domain, resulting in a C-terminal fragment that functions as a dominant negative likely by scavenging critical signaling proteins required for LTD. Thus, the C-terminal portion of PSD-95 serves a dual function. It is required to localize PSD-95 at synapses and as a scaffold for signaling proteins that are required for LTD.

    View details for DOI 10.1016/j.neuron.2007.11.027

    View details for Web of Science ID 000252758400009

    View details for PubMedID 18215622

  • Endocytosis and recycling of AMPA receptors lacking GIuR2/3 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Biou, V., Bhattacharyya, S., Malenka, R. C. 2008; 105 (3): 1038-1043

    Abstract

    Excitatory synapses in the mammalian brain contain two types of ligand-gated ion channels: AMPA receptors (AMPARs) and NMDA receptors (NMDARs). AMPARs are responsible for generating excitatory synaptic responses, whereas NMDAR activation triggers long-lasting changes in these responses by modulating the trafficking of AMPARs toward and away from synapses. AMPARs are tetramers composed of four subunits (GluR1-GluR4), which current models suggest govern distinct AMPAR trafficking behavior during synaptic plasticity. Here, we address the roles of GluR2 and GluR3 in controlling the recycling- and activity-dependent endocytosis of AMPARs by using cultured hippocampal neurons prepared from knockout (KO) mice lacking these subunits. We find that synapses and dendritic spines form normally in cells lacking GluR2/3 and that upon NMDAR activation, GluR2/3-lacking AMPARs are endocytosed in a manner indistinguishable from GluR2-containing AMPARs in wild-type (WT) neurons. AMPARs lacking GluR2/3 also recycle to the plasma membrane identically to WT AMPARs. However, because of their permeability to calcium, GluR2-lacking but not WT AMPARs exhibited robust internalization throughout the dendritic tree in response to AMPA application. Dendritic endocytosis of AMPARs also was observed in GABAergic neurons, which express a high proportion of GluR2-lacking AMPARs. These results demonstrate that GluR2 and GluR3 are not required for activity-dependent endocytosis of AMPARs and suggest that the most important property of GluR2 in the context of AMPAR trafficking may be its influence on calcium permeability.

    View details for DOI 10.1073/pnas.0711412105

    View details for Web of Science ID 000252647900039

    View details for PubMedID 18195348

  • Synaptic plasticity: Multiple forms, functions, and mechanisms NEUROPSYCHOPHARMACOLOGY Citri, A., Malenka, R. C. 2008; 33 (1): 18-41

    Abstract

    Experiences, whether they be learning in a classroom, a stressful event, or ingestion of a psychoactive substance, impact the brain by modifying the activity and organization of specific neural circuitry. A major mechanism by which the neural activity generated by an experience modifies brain function is via modifications of synaptic transmission; that is, synaptic plasticity. Here, we review current understanding of the mechanisms of the major forms of synaptic plasticity at excitatory synapses in the mammalian brain. We also provide examples of the possible developmental and behavioral functions of synaptic plasticity and how maladaptive synaptic plasticity may contribute to neuropsychiatric disorders.

    View details for DOI 10.1038/sj.npp.1301559

    View details for Web of Science ID 000251267100004

    View details for PubMedID 17728696

  • Mechanisms underlying dedepression of synaptic NMDA receptors in the hippocampus JOURNAL OF NEUROPHYSIOLOGY Morishita, W., Malenka, R. C. 2008; 99 (1): 254-263

    Abstract

    N-Methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in hippocampal CA1 pyramidal cells are depressed during NMDAR-dependent long-term depression (LTD) due to mechanisms, in part, distinct from those underlying LTD of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic responses. The mechanisms underlying dedepression of synaptic NMDARs, however, are not known. We find that dedepression of NMDAR-mediated synaptic responses in the CA1 region of the rat hippocampus is input specific and does not require synaptic stimulation to be maintained. The induction of dedepression does not require activation of metabotropic glutamate receptors, L-type Ca(2+) channels, or release of Ca(2+) from intracellular stores. It does, however, rely on activation of NMDARs. In contrast to the dedepression of AMPAR-mediated synaptic responses, dedepression of NMDAR-mediated synaptic responses does not depend on activation of calcium/calmodulin-dependent protein kinase II, protein kinase C, cAMP-dependent protein kinase, or Src kinases. However, dedepression of synaptic NMDARs is significantly impaired by inhibitors of mitogen-activated protein kinase signaling. Specifically, inhibitors of extracellular signal-regulated kinase 1/2 prevented normal dedepression of synaptic NMDARs by a mechanism that did not require protein synthesis. These results provide further evidence that synaptic NMDARs can be bidirectionally modified by activity but by mechanisms distinct from those responsible for the activity-dependent, bidirectional modulation of synaptic AMPARs.

    View details for DOI 10.1152/jn.01011.2007

    View details for Web of Science ID 000252398500022

    View details for PubMedID 17989241

  • Synaptic plasticity and addiction NATURE REVIEWS NEUROSCIENCE Kauer, J. A., Malenka, R. C. 2007; 8 (11): 844-858

    Abstract

    Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.

    View details for DOI 10.1038/nrn2234

    View details for Web of Science ID 000251074700013

    View details for PubMedID 17948030

  • Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Guzman, R., Uchida, N., Bliss, T. M., He, D., Christopherson, K. K., Stellwagen, D., Capela, A., Greve, J., Malenka, R. C., Moseley, M. E., Palmer, T. D., Steinberg, G. K. 2007; 104 (24): 10211-10216

    Abstract

    Noninvasive monitoring of stem cells, using high-resolution molecular imaging, will be instrumental to improve clinical neural transplantation strategies. We show that labeling of human central nervous system stem cells grown as neurospheres with magnetic nanoparticles does not adversely affect survival, migration, and differentiation or alter neuronal electrophysiological characteristics. Using MRI, we show that human central nervous system stem cells transplanted either to the neonatal, the adult, or the injured rodent brain respond to cues characteristic for the ambient microenvironment resulting in distinct migration patterns. Nanoparticle-labeled human central nervous system stem cells survive long-term and differentiate in a site-specific manner identical to that seen for transplants of unlabeled cells. We also demonstrate the impact of graft location on cell migration and describe magnetic resonance characteristics of graft cell death and subsequent clearance. Knowledge of migration patterns and implementation of noninvasive stem cell tracking might help to improve the design of future clinical neural stem cell transplantation.

    View details for DOI 10.1073/pnas.0608519104

    View details for Web of Science ID 000247363000053

    View details for PubMedID 17553967

  • Mechanisms for synapse specificity during striatal long-term depression JOURNAL OF NEUROSCIENCE Singla, S., Kreitzer, A. C., Malenka, R. C. 2007; 27 (19): 5260-5264

    Abstract

    Endocannabinoid (eCB)-mediated forms of long-term synaptic plasticity occur in several brain regions, but much remains unknown about their basic properties and underlying mechanisms. Here, we present evidence that eCB-mediated long-term depression (eCB-LTD) at excitatory synapses on medium spiny neurons in the striatum requires presynaptic activity coincident with CB1 receptor activation. This dual requirement for CB1 activation and presynaptic activity is a mechanism by which eCB-LTD may be made synapse specific.

    View details for DOI 10.1523/JNEUROSCI.0018-07.2007

    View details for Web of Science ID 000246358500027

    View details for PubMedID 17494712

  • Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome NATURE NEUROSCIENCE Fernandez, F., Morishita, W., Zuniga, E., Nguyen, J., Blank, M., Malenka, R. C., Garner, C. C. 2007; 10 (4): 411-413

    Abstract

    Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.

    View details for DOI 10.1038/nn1860

    View details for Web of Science ID 000245228600008

    View details for PubMedID 17322876

  • Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression NEUROPHARMACOLOGY Morishita, W., Lu, W., Smith, G. B., Nic, R. A., Bear, M. F., Malenka, R. C. 2007; 52 (1): 71-76

    Abstract

    The triggering of both NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus requires a rise in postsynaptic calcium. A prominent hypothesis has been that the detailed properties of this postsynaptic calcium signal dictate whether LTP or LTD is generated by a given pattern of synaptic activity. Recently, however, evidence has been presented that the subunit composition of the NMDA receptor (NMDAR) determines whether a synapse undergoes LTP or LTD with NR2A-containing NMDARs triggering LTP and NR2B-containing NMDARs triggering LTD. In the present study, the role of NR2B-containing synaptic NMDARs in the induction of LTD in CA1 pyramidal cells has been studied using the selective NR2B antagonists, ifenprodil and Ro25-6981. While both antagonists reduced NMDAR-mediated synaptic currents, neither prevented induction of LTD. These results demonstrate that activation of NR2B-containing NMDARs is not an absolute requirement for the induction of LTD in the hippocampus.

    View details for DOI 10.1016/j.neuropharm.2006.07.005

    View details for Web of Science ID 000243698200008

    View details for PubMedID 16899258

  • Genetic analysis of Mint/X11 proteins: Essential presynaptic functions of a neuronal adaptor protein family JOURNAL OF NEUROSCIENCE Ho, A., Morishita, W., Atasoy, D., Liu, X., Tabuchi, K., Hammer, R. E., Malenka, R. C., Sudhof, T. C. 2006; 26 (50): 13089-13101

    Abstract

    Mints/X11s are adaptor proteins composed of three isoforms: neuron-specific Mints 1 and 2, and the ubiquitously expressed Mint 3. We have now analyzed constitutive and conditional knock-out mice for all three Mints/X11s. We found that approximately 80% of mice lacking both neuron-specific Mint isoforms (Mints 1 and 2) die at birth, whereas mice lacking any other combination of Mint isoforms survive normally. The approximately 20% surviving Mint 1/2 double knock-out mice exhibit a decrease in weight and deficits in motor behaviors. Hippocampal slice electrophysiology uncovered a decline in spontaneous neurotransmitter release, lowered synaptic strength, and enhanced paired-pulse facilitation in Mint-deficient mice, suggesting a decreased presynaptic release probability. Acute ablation of Mint expression in cultured neurons from conditional Mint 1/2/3 triple knock-in mice also revealed a decline in spontaneous release, confirming that deletion of Mints impair presynaptic function. Quantitation of synaptic proteins showed that acute deletion of Mints caused a selective increase in Munc18-1 and Fe65 proteins, and overexpression of Munc18-1 in wild-type neurons also produced a decrease in spontaneous release, suggesting that the interaction of Mints with Munc18-1 may contribute to the presynaptic phenotype observed in Mint-deficient mice. Our studies thus indicate that Mints are important regulators of presynaptic neurotransmitter release that are essential for mouse survival.

    View details for DOI 10.1523/JNEUROSCI.2855-06.2006

    View details for Web of Science ID 000242996200024

    View details for PubMedID 17167098

  • Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function NEURON Schlueter, O. M., Xu, W., Malenka, R. C. 2006; 51 (1): 99-111

    Abstract

    PSD-95 and SAP97 are scaffolding proteins that have been implicated in regulating AMPA receptor incorporation and function at synapses. Gain- and loss-of-function approaches, however, have generated conflicting results. To minimize adaptations during development and potential dominant-negative effects of overexpression, we have combined silencing of endogenous PSD-95 in mature neurons with heterologous expression of specific SAP97 or PSD-95 isoforms. We find that both PSD-95 and SAP97 contain alternative N termini expressing either double cysteines that normally are palmitoylated (alpha-isoforms) or an L27 domain (beta-isoforms). Whereas alpha-isoforms of PSD-95 and SAP97 influence AMPA receptor-mediated synaptic strength independent of activity, the effects of beta-isoforms are regulated by activity in a CaMKII-dependent manner. Importantly, the synaptic effects of the beta-isoforms are masked by the endogenous alpha-isoform of PSD-95. These results demonstrate that the different N termini of the predominant endogenous forms of PSD-95 (alpha-isoform) and SAP97 (beta-isoform) govern their role in regulating synaptic function.

    View details for DOI 10.1016/j.neuron.2006.05.016

    View details for Web of Science ID 000239037700013

    View details for PubMedID 16815335

  • Neuronal pentraxins mediate synaptic refinement in the developing visual system JOURNAL OF NEUROSCIENCE Bjartmar, L., Huberman, A. D., Ullian, E. M., Renteria, R. C., Liu, X., Xu, W., Prezioso, J., Susman, M. W., Stellwagen, D., Stokes, C. C., Cho, R., Worley, P., Malenka, R. C., Ball, S., Peachey, N. S., Copenhagen, D., Chapman, B., Nakamoto, M., Barres, B. A., Perin, M. S. 2006; 26 (23): 6269-6281

    Abstract

    Neuronal pentraxins (NPs) define a family of proteins that are homologous to C-reactive and acute-phase proteins in the immune system and have been hypothesized to be involved in activity-dependent synaptic plasticity. To investigate the role of NPs in vivo, we generated mice that lack one, two, or all three NPs. NP1/2 knock-out mice exhibited defects in the segregation of eye-specific retinal ganglion cell (RGC) projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation and elimination. Retinas from mice lacking NP1 and NP2 had cholinergically driven waves of activity that occurred at a frequency similar to that of wild-type mice, but several other parameters of retinal activity were altered. RGCs cultured from these mice exhibited a significant delay in functional maturation of glutamatergic synapses. Other developmental processes, such as pathfinding of RGCs at the optic chiasm and hippocampal long-term potentiation and long-term depression, appeared normal in NP-deficient mice. These data indicate that NPs are necessary for early synaptic refinements in the mammalian retina and dorsal lateral geniculate nucleus. We speculate that NPs exert their effects through mechanisms that parallel the known role of short pentraxins outside the CNS.

    View details for DOI 10.1523/jneurosci.4212-05.2006

    View details for Web of Science ID 000238174600017

    View details for PubMedID 16763034

  • Substrate localization creates specificity in calcium/calmodulin-dependent protein kinase II signaling at synapses JOURNAL OF BIOLOGICAL CHEMISTRY Tsui, J., Malenka, R. C. 2006; 281 (19): 13794-13804

    Abstract

    Calcium/calmodulin-dependent protein kinase II (CaMKII), a major component of the postsynaptic density (PSD) of excitatory synapses, plays a key role in the regulation of synaptic function in the mammalian brain. Although many postsynaptic substrates for CaMKII have been characterized in vitro, relatively little is known about their phosphorylation in vivo. By tagging synaptic proteins with a peptide substrate specific for CaMKII and expressing them in cultured neurons, we have visualized substrate phosphorylation by CaMKII at intact synapses. All substrates tested were strongly phosphorylated by CaMKII in HEK293 cells. However, activity-dependent phosphorylation of substrates at synapses was highly selective in that the glutamate receptor subunits NR2B and GluR1 were poorly phosphorylated whereas PSD-95 and Stargazin, proteins implicated in the scaffolding and trafficking of AMPA receptors, were robustly phosphorylated. Phosphatase activity limited phosphorylation of Stargazin but not NR2B and GluR1. These results suggest that the unique molecular architecture of the PSD results in highly selective substrate discrimination by CaMKII.

    View details for DOI 10.1074/jbc.M600966200

    View details for Web of Science ID 000237336600090

    View details for PubMedID 16551613

  • Synaptic scaling mediated by glial TNF-alpha NATURE Stellwagen, D., Malenka, R. C. 2006; 440 (7087): 1054-1059

    Abstract

    Two general forms of synaptic plasticity that operate on different timescales are thought to contribute to the activity-dependent refinement of neural circuitry during development: (1) long-term potentiation (LTP) and long-term depression (LTD), which involve rapid adjustments in the strengths of individual synapses in response to specific patterns of correlated synaptic activity, and (2) homeostatic synaptic scaling, which entails uniform adjustments in the strength of all synapses on a cell in response to prolonged changes in the cell's electrical activity. Without homeostatic synaptic scaling, neural networks can become unstable and perform suboptimally. Although much is known about the mechanisms underlying LTP and LTD, little is known about the mechanisms responsible for synaptic scaling except that such scaling is due, at least in part, to alterations in receptor content at synapses. Here we show that synaptic scaling in response to prolonged blockade of activity is mediated by the pro-inflammatory cytokine tumour-necrosis factor-alpha (TNF-alpha). Using mixtures of wild-type and TNF-alpha-deficient neurons and glia, we also show that glia are the source of the TNF-alpha that is required for this form of synaptic scaling. We suggest that by modulating TNF-alpha levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.

    View details for DOI 10.1038/nature04671

    View details for Web of Science ID 000236906000037

    View details for PubMedID 16547515

  • CREB modulates excitability of nucleus accumbens neurons NATURE NEUROSCIENCE Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E. J., Malenka, R. C. 2006; 9 (4): 475-477

    Abstract

    Drugs of abuse cause activation of the cyclic AMP response element binding protein (CREB) in the nucleus accumbens (NAc). Expression of active CREB in rat NAc medium spiny neurons (MSNs) increased their excitability, whereas dominant-negative CREB had the opposite effect. Decreasing excitability of NAc MSNs in vivo by overexpression of potassium channels enhanced locomotor responses to cocaine, suggesting that the increased NAc MSN excitability caused by CREB helped to limit behavioral sensitivity to cocaine.

    View details for DOI 10.1038/nn1661

    View details for Web of Science ID 000236310700010

    View details for PubMedID 16520736

  • Transsynaptic signaling by postsynaptic synapse-associated protein 97 JOURNAL OF NEUROSCIENCE Regalado, M. P., Terry-Lorenzo, R. T., Waites, C. L., Garner, C. C., Malenka, R. C. 2006; 26 (8): 2343-2357

    Abstract

    The molecular mechanisms by which postsynaptic modifications lead to precisely coordinated changes in presynaptic structure and function are primarily unknown. To address this issue, we examined the presynaptic consequences of postsynaptic expression of members of the membrane-associated guanylate kinase family of synaptic scaffolding proteins. Postsynaptic expression of synapse-associated protein 97 (SAP97) increased presynaptic protein content and active zone size to a greater extent than comparable amounts of postsynaptic PSD-95 (postsynaptic density-95) or SAP102. In addition, postsynaptic expression of SAP97 enhanced presynaptic function, as measured by increased FM4-64 dye uptake. The structural presynaptic effects of postsynaptic SAP97 required ligand binding through two of its PDZ (PSD-95/Discs large/zona occludens-1) domains as well as intact N-terminal and guanylate kinase domains. Expression of SAP97 recruited a complex of additional postsynaptic proteins to synapses including glutamate receptor 1, Shank1a, SPAR (spine-associated RapGAP), and proSAP2. Furthermore, inhibition of several different transsynaptic signaling proteins including cadherins, integrins, and EphB receptor/ephrinB significantly reduced the presynaptic growth caused by postsynaptic SAP97. These results suggest that SAP97 may play a central role in the coordinated growth of synapses during development and plasticity by recruiting a complex of postsynaptic proteins that enhances presynaptic terminal growth and function via multiple transsynaptic molecular interactions.

    View details for DOI 10.1523/JNEUROSCI.5247-05.2006

    View details for Web of Science ID 000235515800024

    View details for PubMedID 16495462

  • Neural mechanisms of addiction: The role of reward-related learning and memory ANNUAL REVIEW OF NEUROSCIENCE Hyman, S. E., Malenka, R. C., Nestler, E. J. 2006; 29: 565-598

    Abstract

    Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.

    View details for DOI 10.1146/annurev.neuro.29.051605.113009

    View details for Web of Science ID 000239807800020

    View details for PubMedID 16776597

  • A schizophrenia-related sensorimotor deficit links alpha 3-containing GABA(A) receptors to a dopamine hyperfunction PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yee, B. K., Keist, R., von Boehmer, L., Studer, R., Benke, D., Hagenbuch, N., Dong, Y., Malenka, R. C., Fritschy, J. M., Bluethmann, H., Feldon, J., Mohler, H., Rudolph, U. 2005; 102 (47): 17154-17159

    Abstract

    Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.

    View details for DOI 10.1073/pnas.0508752102

    View details for Web of Science ID 000233463200045

    View details for PubMedID 16284244

  • Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum JOURNAL OF NEUROSCIENCE Kreitzer, A. C., Malenka, R. C. 2005; 25 (45): 10537-10545

    Abstract

    Endocannabinoids are important mediators of short- and long-term synaptic plasticity, but the mechanisms of endocannabinoid release have not been studied extensively outside the hippocampus and cerebellum. Here, we examined the mechanisms of endocannabinoid-mediated long-term depression (eCB-LTD) in the dorsal striatum, a brain region critical for motor control and reinforcement learning. Unlike other cell types, strong depolarization of medium spiny neurons was not sufficient to yield detectable endocannabinoid release. However, when paired with postsynaptic depolarization sufficient to activate L-type calcium channels, activation of postsynaptic metabotropic glutamate receptors (mGluRs), either by high-frequency tetanic stimulation or an agonist, induced eCB-LTD. Pairing bursts of afferent stimulation with brief subthreshold membrane depolarizations that mimicked down-state to up-state transitions also induced eCB-LTD, which not only required activation of mGluRs and L-type calcium channels but also was bidirectionally modulated by dopamine D2 receptors. Consistent with network models, these results demonstrate that dopamine regulates the induction of a Hebbian form of long-term synaptic plasticity in the striatum. However, this gating of plasticity by dopamine is accomplished via an unexpected mechanism involving the regulation of mGluR-dependent endocannabinoid release.

    View details for DOI 10.1523/JNEUROSCI.2959-05.2005

    View details for Web of Science ID 000233137000025

    View details for PubMedID 16280591

  • The role of synaptic plasticity in addiction CLINICAL NEUROSCIENCE RESEARCH Saal, D., Malenka, R. C. 2005; 5 (2-4): 141-146
  • GABA excitation in the adult brain: A mechanism for excitation-neurogenesis coupling NEURON Deisseroth, K., Malenka, R. C. 2005; 47 (6): 775-777

    Abstract

    The production of new neurons in the adult hippocampus is exquisitely regulated, and alterations in this process may underlie both normal and pathological hippocampal function. In this issue of Neuron, Tozuka et al. describe electrophysiological recordings that target proliferating progenitor cells in adult mouse hippocampal slices. They report that GABAergic synaptic inputs directly depolarize the proliferating progenitors, thereby activating molecular players that favor neuronal differentiation and providing a mechanism for direct excitation-neurogenesis coupling in vivo.

    View details for DOI 10.1016/j.neuron.2005.08.029

    View details for Web of Science ID 000232085000003

    View details for PubMedID 16157270

  • Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses NATURE NEUROSCIENCE Morishita, W., Marie, H., Malenka, R. C. 2005; 8 (8): 1043-1050

    Abstract

    Although long-term depression (LTD) of AMPA receptor-mediated postsynaptic currents (AMPAR EPSCs) has been extensively examined, little is known about the mechanisms responsible for LTD of NMDA receptor (NMDAR)-mediated EPSCs. Here we show differences in the intracellular signaling cascades that mediate LTD of AMPAR EPSCs versus NMDAR EPSCs in rat hippocampus. Both forms of LTD were blocked by inhibitors of protein phosphatase 1, but only LTD of AMPAR EPSCs was affected by inhibition of calcineurin. Notably, in contrast to LTD of AMPAR EPSCs, LTD of NMDAR EPSCs was unaffected by endocytosis inhibitors. A role for calcium-dependent actin depolymerization in LTD of NMDAR EPSCs was supported by the findings that the actin stabilizer phalloidin and a cofilin inhibitory peptide each blocked LTD of NMDAR EPSCs but not AMPAR EPSCs. These results suggest that the same pattern of afferent activity elicits depression of AMPAR- and NMDAR-mediated synaptic responses by means of distinct triggering and expression mechanisms.

    View details for DOI 10.1038/nn1506

    View details for Web of Science ID 000230760200016

    View details for PubMedID 16025109

  • Generation of silent synapses by acute in vivo expression of CaMKIV and CREB NEURON Marie, H., Morishita, W., Yu, X., Calakos, N., Malenka, R. C. 2005; 45 (5): 741-752

    Abstract

    The transcription factor CREB is critical for several forms of experience-dependent plasticity in a range of species and is commonly activated in neurons by calcium/calmodulin-dependent protein kinase IV (CaMKIV). Surprisingly, little is known about the neural circuit adaptations caused by activation of CaMKIV and CREB. Here, we use viral-mediated gene transfer in vivo to examine the consequences of acute expression of constitutively active forms of CaMKIV and CREB on synaptic function in the rodent hippocampus. Acute expression of active CaMKIV or CREB caused an enhancement of both NMDA receptor-mediated synaptic responses and long-term potentiation (LTP). This was accompanied by electrophysiological and morphological changes consistent with the generation of "silent synapses," which provide an ideal substrate for further experience-dependent modifications of neural circuitry and which may also be important for the consolidation of long-term synaptic plasticity and memories.

    View details for DOI 10.1016/j.neuron.2005.01.039

    View details for Web of Science ID 000227446700013

    View details for PubMedID 15748849

  • Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: Adaptations in potassium currents JOURNAL OF NEUROSCIENCE Dong, Y., Nasif, F. J., Tsui, J. J., Ju, W. Y., Cooper, D. C., Hu, X. T., Malenka, R. C., White, F. J. 2005; 25 (4): 936-940

    Abstract

    Drug-induced adaptations in the prefrontal cortex (PFC) contribute to several core aspects of addictive behaviors, but the underlying neuronal processes remain essentially unknown. Here, we demonstrate that repeated in vivo exposure to cocaine persistently reduces the voltage-gated K+ current (VGKC) in PFC pyramidal neurons, resulting in enhanced membrane excitability. Analysis of dopamine D1-class receptor (D1R)-mediated modulation of VGKC indicates that, despite the absence of direct D1R stimulation, downstream D1 signaling (the cAMP/protein kinase A pathway) is increased during withdrawal from chronic cocaine treatment and plays a central role in the drug-induced membrane plasticity in PFC. This long-lasting, cocaine-induced plasticity of membrane excitability in PFC pyramidal neurons may contribute to the impaired decision making and drug craving that characterize cocaine withdrawal.

    View details for DOI 10.1523/JNEUROSCI.4715-04.2005

    View details for Web of Science ID 000226577000019

    View details for PubMedID 15673674

  • LTP and LTD: An embarrassment of riches NEURON Malenka, R. C., Bear, M. F. 2004; 44 (1): 5-21

    Abstract

    LTP and LTD, the long-term potentiation and depression of excitatory synaptic transmission, are widespread phenomena expressed at possibly every excitatory synapse in the mammalian brain. It is now clear that "LTP" and "LTD" are not unitary phenomena. Their mechanisms vary depending on the synapses and circuits in which they operate. Here we review those forms of LTP and LTD for which mechanisms have been most firmly established. Examples are provided that show how these mechanisms can contribute to experience-dependent modifications of brain function.

    View details for Web of Science ID 000224232600003

    View details for PubMedID 15450156

  • Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: Electrophysiological and behavioral correlates in individual rats JOURNAL OF NEUROSCIENCE Borgland, S. L., Malenka, R. C., Bonci, A. 2004; 24 (34): 7482-7490

    Abstract

    The initiation of the psychostimulant sensitization process depends on the mesolimbic system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens. Although such initiation is primarily dependent on glutamatergic activity in VTA neurons, the exact role VTA excitatory synapses play in this process is poorly understood. Here, we examine the effects of repeated in vivo injections of cocaine on the magnitude and duration of the increase in strength at VTA excitatory synapses reported previously to be elicited by a single in vivo exposure to cocaine (Ungless et al., 2001; Saal et al., 2003). We also compare the synaptic modifications induced by cocaine with its effects on locomotor activity. Surprisingly, repeated cocaine exposure potentiated the ratio of AMPA receptor-mediated to NMDA receptor-mediated EPSCs to a similar extent and duration as a single in vivo cocaine exposure. In naive animals, the magnitude of the cocaine-induced locomotor activity after a single injection of cocaine correlated with the magnitude of the accompanying synaptic enhancement. This correlation was lost on the seventh day of repeated cocaine administration, as well as when a challenge injection was given 10 d after the cessation of repeated cocaine administration. These results suggest that the cocaine-induced synaptic plasticity at VTA excitatory synapses is transient, and its duration depends on the last exposure to cocaine. Furthermore, chronic cocaine exposure disrupts the normal, presumably adaptive relationship between synaptic enhancement in the VTA and behavior.

    View details for DOI 10.1523/JNEUROSCI.1312-04.2004

    View details for Web of Science ID 000223521200008

    View details for PubMedID 15329395

  • Multiple roles for the active zone protein RIM1 alpha in late stages of neurotransmitter release NEURON Calakos, N., Schoch, S., Sudhof, T. C., Malenka, R. C. 2004; 42 (6): 889-896

    Abstract

    The active zone protein RIM1alpha interacts with multiple active zone and synaptic vesicle proteins and is implicated in short- and long-term synaptic plasticity, but it is unclear how RIM1alpha's biochemical interactions translate into physiological functions. To address this question, we analyzed synaptic transmission in autaptic neurons cultured from RIM1alpha-/- mice. Deletion of RIM1alpha causes a large reduction in the readily releasable pool of vesicles, alters short-term plasticity, and changes the properties of evoked asynchronous release. Lack of RIM1alpha, however, had no effect on synapse formation, spontaneous release, overall Ca2+ sensitivity of release, or synaptic vesicle recycling. These results suggest that RIM1alpha modulates sequential steps in synaptic vesicle exocytosis through serial protein-protein interactions and that this modulation is the basis for RIM1alpha's role in synaptic plasticity.

    View details for Web of Science ID 000222329300005

    View details for PubMedID 15207234

  • Excitation-neurogenesis coupling in adult neural stem/progenitor cells NEURON Deisseroth, K., Singla, S., Toda, H., Monje, M., Palmer, T. D., Malenka, R. C. 2004; 42 (4): 535-552

    Abstract

    A wide variety of in vivo manipulations influence neurogenesis in the adult hippocampus. It is not known, however, if adult neural stem/progenitor cells (NPCs) can intrinsically sense excitatory neural activity and thereby implement a direct coupling between excitation and neurogenesis. Moreover, the theoretical significance of activity-dependent neurogenesis in hippocampal-type memory processing networks has not been explored. Here we demonstrate that excitatory stimuli act directly on adult hippocampal NPCs to favor neuron production. The excitation is sensed via Ca(v)1.2/1.3 (L-type) Ca(2+) channels and NMDA receptors on the proliferating precursors. Excitation through this pathway acts to inhibit expression of the glial fate genes Hes1 and Id2 and increase expression of NeuroD, a positive regulator of neuronal differentiation. These activity-sensing properties of the adult NPCs, when applied as an "excitation-neurogenesis coupling rule" within a Hebbian neural network, predict significant advantages for both the temporary storage and the clearance of memories.

    View details for Web of Science ID 000221708300006

    View details for PubMedID 15157417

  • Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors NATURE NEUROSCIENCE Ju, W., Morishita, W., Tsui, J., Gaietta, G., Deerinck, T. J., Adams, S. R., Garner, C. C., Tsien, R. Y., Ellisman, M. H., Malenka, R. C. 2004; 7 (3): 244-253

    Abstract

    Regulation of AMPA receptor (AMPAR) trafficking is important for neural plasticity. Here we examined the trafficking and synthesis of the GluR1 and GluR2 subunits using ReAsH-EDT(2) and FlAsH-EDT(2) staining. Activity blockade of rat cultured neurons increased dendritic GluR1, but not GluR2, levels. Examination of transected dendrites revealed that both AMPAR subunits were synthesized in dendrites and that activity blockade enhanced dendritic synthesis of GluR1 but not GluR2. In contrast, acute pharmacological manipulations increased dendritic synthesis of both subunits. AMPARs synthesized in dendrites were inserted into synaptic plasma membranes and, after activity blockade, the electrophysiological properties of native synaptic AMPARs changed in the manner predicted by the imaging experiments. In addition to providing a novel mechanism for synaptic modifications, these results point out the advantages of using FlAsH-EDT(2) and ReAsH-EDT(2) for studying the trafficking of newly synthesized proteins in local cellular compartments such as dendrites.

    View details for DOI 10.1038/nn1189

    View details for Web of Science ID 000189197900014

    View details for PubMedID 14770185

  • The addicted brain SCIENTIFIC AMERICAN Nestler, E. J., Malenka, R. C. 2004; 290 (3): 78-85

    View details for Web of Science ID 000188888600034

    View details for PubMedID 14981881

  • beta-catenin is critical for dendritic morphogenesis NATURE NEUROSCIENCE Yu, X., Malenka, R. C. 2003; 6 (11): 1169-1177

    Abstract

    Regulated growth and arborization of dendritic processes are critical to the formation of functional neuronal networks. Here we identify beta-catenin as a critical mediator of dendritic morphogenesis. We found that increasing the intracellular levels of beta-catenin and other members of the cadherin/catenin complex, namely N-cadherin and alphaN-catenin, enhances dendritic arborization in rat hippocampal neurons, an effect that does not require Wnt/beta-catenin-dependent transcription. Conversely, proteins that sequester beta-catenin decreased dendritic branch tip number and total dendritic branch length. Enhancement of dendritic growth elicited by depolarization requires beta-catenin and increased Wnt release. These results identify Wnt/beta-catenin signaling as an important mediator of dendritic development and suggest that the intracellular level of the cadherin/catenin complex is a limiting factor during critical stages of dendritic morphogenesis.

    View details for DOI 10.1038/nn1132

    View details for Web of Science ID 000186229200016

    View details for PubMedID 14528308

  • Opinion - The long-term potential of LTP NATURE REVIEWS NEUROSCIENCE Malenka, R. C. 2003; 4 (11): 923-926

    View details for DOI 10.1038/nrn1249

    View details for Web of Science ID 000186362300018

    View details for PubMedID 14595403

  • Synaptic plasticity in the mesolimbic dopamine system PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Thomas, M. J., Malenka, R. C. 2003; 358 (1432): 815-819

    Abstract

    Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

    View details for DOI 10.1098/rstb.2002.1236

    View details for Web of Science ID 000182654100028

    View details for PubMedID 12740128

  • Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons NEURON Saal, D., Dong, Y., Bonci, A., Malenka, R. C. 2003; 37 (4): 577-582

    Abstract

    Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.

    View details for Web of Science ID 000181136500007

    View details for PubMedID 12597856

  • A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ho, A., Morishita, W., Hammer, R. E., Malenka, R. C., Sudhof, T. C. 2003; 100 (3): 1409-1414

    Abstract

    Mints (also called X11-like proteins) are adaptor proteins composed of divergent N-terminal sequences that bind to synaptic proteins such as CASK (Mint 1 only) and Munc18-1 (Mints 1 and 2) and conserved C-terminal PTB- and PDZ-domains that bind to widely distributed proteins such as APP, presenilins, and Ca(2+) channels (all Mints). We find that Mints 1 and 2 are similarly expressed in most neurons except for inhibitory interneurons that contain selectively high levels of Mint 1. Using knockout mice, we show that deletion of Mint 1 does not impair survival or alter the overall brain architecture, arguing against an essential developmental function of the Mint 1-CASK complex. In electrophysiological recordings in the hippocampus, we observed no changes in short- or long-term synaptic plasticity in excitatory synapses from Mint 1-deficient mice and detected no alterations in the ratio of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents. Thus the Mint 1-CASK complex is not required for AMPA- and NMDA-receptor functions or for synaptic plasticity in excitatory synapses. In inhibitory synapses, however, we uncovered an approximately 3-fold increase in presynaptic paired-pulse depression, suggesting that deletion of Mint 1 impairs the regulation of gamma-aminobutyric acid release. Our data indicate that Mints 1 and 2 perform redundant synaptic functions that become apparent in Mint 1-deficient mice in inhibitory interneurons because these neurons selectively express higher levels of Mint 1 than Mint 2.

    View details for DOI 10.1073/pnas.252774899

    View details for Web of Science ID 000180838100114

    View details for PubMedID 12547917

  • A developmental switch in the signaling cascades for LTP induction NATURE NEUROSCIENCE Yasuda, H., Barth, A. L., Stellwagen, D., Malenka, R. C. 2003; 6 (1): 15-16

    Abstract

    Long-term potentiation (LTP) is thought to be critically involved not only in learning and memory, but also during the activity-dependent developmental phases of neural circuit formation and refinement. Whether the mechanisms underlying LTP change during this phase of postnatal development, however, is unknown. We report here that, unlike LTP in the more mature CA1 region of the hippocampus, LTP in neonatal rodent hippocampus (<9 postnatal days,

    View details for DOI 10.1038/nn985

    View details for Web of Science ID 000180089300008

    View details for PubMedID 12469130

  • Control of synaptic strength by glial TNF alpha SCIENCE Beattie, E. C., Stellwagen, D., Morishita, W., Bresnahan, J. C., Ha, B. K., von Zastrow, M., Beattie, M. S., Malenka, R. C. 2002; 295 (5563): 2282-2285

    Abstract

    Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.

    View details for Web of Science ID 000174561700051

    View details for PubMedID 11910117

  • RIM1 alpha is required for presynaptic long-term potentiation NATURE Castillo, P. E., Schoch, S., Schmitz, F., Sudhof, T. C., Malenka, R. C. 2002; 415 (6869): 327-330

    Abstract

    Two main forms of long-term potentiation (LTP)-a prominent model for the cellular mechanism of learning and memory-have been distinguished in the mammalian brain. One requires activation of postsynaptic NMDA (N-methyl d-aspartate) receptors, whereas the other, called mossy fibre LTP, has a principal presynaptic component. Mossy fibre LTP is expressed in hippocampal mossy fibre synapses, cerebellar parallel fibre synapses and corticothalamic synapses, where it apparently operates by a mechanism that requires activation of protein kinase A. Thus, presynaptic substrates of protein kinase A are probably essential in mediating this form of long-term synaptic plasticity. Studies of knockout mice have shown that the synaptic vesicle protein Rab3A is required for mossy fibre LTP, but the protein kinase A substrates rabphilin, synapsin I and synapsin II are dispensable. Here we report that mossy fibre LTP in the hippocampus and the cerebellum is abolished in mice lacking RIM1alpha, an active zone protein that binds to Rab3A and that is also a protein kinase A substrate. Our results indicate that the long-term increase in neurotransmitter release during mossy fibre LTP may be mediated by a unitary mechanism that involves the GTP-dependent interaction of Rab3A with RIM1alpha at the interface of synaptic vesicles and the active zone.

    View details for Web of Science ID 000173293500045

    View details for PubMedID 11797010

  • RIM1 alpha forms a protein scaffold for regulating neurotransmitter release at the active zone NATURE Schoch, S., Castillo, P. E., Jo, T., Mukherjee, K., Geppert, M., Wang, Y., Schmitz, F., Malenka, R. C., Sudhof, T. C. 2002; 415 (6869): 321-326

    Abstract

    Neurotransmitters are released by synaptic vesicle fusion at the active zone. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1alpha, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A, interacts with several active zone molecules, including Munc13-1 (ref. 6) and alpha-liprins, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1alpha in mice shows that RIM1alpha is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1alpha has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.

    View details for Web of Science ID 000173293500044

    View details for PubMedID 11797009

  • AMPA receptor trafficking and synaptic plasticity ANNUAL REVIEW OF NEUROSCIENCE Malinow, R., Malenka, R. C. 2002; 25: 103-126

    Abstract

    Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.

    View details for DOI 10.1146/annurev.neuro.25.112701.142758

    View details for Web of Science ID 000177354800003

    View details for PubMedID 12052905

  • Regulation of synaptic strength by protein phosphatase 1 NEURON Morishita, W., Connor, J. H., Xia, H., Quinlan, E. M., Shenolikar, S., Malenka, R. C. 2001; 32 (6): 1133-1148

    Abstract

    We investigated the role of postsynaptic protein phosphatase 1 (PP1) in regulating synaptic strength by loading CA1 pyramidal cells either with peptides that disrupt PP1 binding to synaptic targeting proteins or with active PP1. The peptides blocked synaptically evoked LTD but had no effect on basal synaptic currents mediated by either AMPA or NMDA receptors. They did, however, cause an increase in synaptic strength following the induction of LTD. Similarly, PP1 had no effect on basal synaptic strength but enhanced LTD. In cultured neurons, synaptic activation of NMDA receptors increased the proportion of PP1 localized to synapses. These results suggest that PP1 does not significantly regulate basal synaptic strength. Appropriate NMDA receptor activation, however, allows PP1 to gain access to synaptic substrates and be recruited to synapses where its activity is necessary for sustaining LTD.

    View details for Web of Science ID 000172886800018

    View details for PubMedID 11754843

  • Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine NATURE NEUROSCIENCE Thomas, M. J., Beurrier, C., Bonci, A., Malenka, R. C. 2001; 4 (12): 1217-1223

    Abstract

    A compelling model of experience-dependent plasticity is the long-lasting sensitization to the locomotor stimulatory effects of drugs of abuse. Adaptations in the nucleus accumbens (NAc), a component of the mesolimbic dopamine system, are thought to contribute to this behavioral change. Here we examine excitatory synaptic transmission in NAc slices prepared from animals displaying sensitization 10-14 days after repeated in vivo cocaine exposure. The ratio of AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) receptor- to NMDA (N-methyl-d-aspartate) receptor-mediated excitatory postsynaptic currents (EPSCs) was decreased at synapses made by prefrontal cortical afferents onto medium spiny neurons in the shell of the NAc. The amplitude of miniature EPSCs at these synapses also was decreased, as was the magnitude of long-term depression. These data suggest that chronic in vivo administration of cocaine elicits a long-lasting depression of excitatory synaptic transmission in the NAc, a change that may contribute to behavioral sensitization and addiction.

    View details for Web of Science ID 000172525000018

    View details for PubMedID 11694884

  • Addiction and the brain: The neurobiology of compulsion and its persistence NATURE REVIEWS NEUROSCIENCE Hyman, S. E., Malenka, R. C. 2001; 2 (10): 695-703

    Abstract

    People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can include tolerance to some drug effects, sensitization to others, and an adapted state - dependence - which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue. Addiction is characterized by a long-lasting risk of relapse, which is often initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory.

    View details for Web of Science ID 000171454000016

    View details for PubMedID 11584307

  • Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons NATURE Ungless, M. A., Whistler, J. L., Malenka, R. C., Bonci, A. 2001; 411 (6837): 583-587

    Abstract

    How do drugs of abuse modify neural circuitry and thereby lead to addictive behaviour? As for many forms of experience-dependent plasticity, modifications in glutamatergic synaptic transmission have been suggested to be particularly important. Evidence of such changes in response to in vivo administration of drugs of abuse is lacking, however. Here we show that a single in vivo exposure to cocaine induces long-term potentiation of AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated currents at excitatory synapses onto dopamine cells in the ventral tegmental area. Potentiation is still observed 5 but not 10 days after cocaine exposure and is blocked when an NMDA (N-methyl-d-aspartate) receptor antagonist is administered with cocaine. Furthermore, long-term potentiation at these synapses is occluded and long-term depression is enhanced by in vivo cocaine exposure. These results show that a prominent form of synaptic plasticity can be elicited by a single in vivo exposure to cocaine and therefore may be involved in the early stages of the development of drug addiction.

    View details for Web of Science ID 000168982500051

    View details for PubMedID 11385572

  • Role of AMPA receptor endocytosis in synaptic plasticity NATURE REVIEWS NEUROSCIENCE Carroll, R. C., Beattie, E. C., von Zastrow, M., Malenka, R. C. 2001; 2 (5): 315-324

    Abstract

    Activity-mediated changes in the strength of synaptic communication are important for the establishment of proper neuronal connections during development and for the experience-dependent modification of neural circuitry that is believed to underlie all forms of behavioural plasticity. Owing to the wide-ranging significance of synaptic plasticity, considerable efforts have been made to identify the mechanisms by which synaptic changes are triggered and expressed. New evidence indicates that one important expression mechanism of several long-lasting forms of synaptic plasticity might involve the physical transport of AMPA-type glutamate receptors in and out of the synaptic membrane. Here, we focus on the rapidly accumulating evidence that AMPA receptors undergo regulated endocytosis, which is important for long-term depression.

    View details for Web of Science ID 000168622800015

    View details for PubMedID 11331915

  • Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD NATURE NEUROSCIENCE Beattie, E. C., Carroll, R. C., Yu, X., Morishita, W., Yasuda, H., von Zastrow, M., Malenka, R. C. 2000; 3 (12): 1291-1300

    Abstract

    The endocytosis of AMPA receptors is thought to be important in the expression of long-term depression (LTD) triggered by NMDA receptor activation. Although signaling pathways necessary for LTD induction have been identified, those responsible for the regulated internalization of AMPA receptors are unknown. Here we show that activation of NMDA receptors alone can trigger AMPA receptor endocytosis through calcium influx and activation of the calcium-dependent protein phosphatase calcineurin. A distinct signaling mechanism mediates the AMPA receptor endocytosis stimulated by insulin. These results demonstrate that although multiple signaling pathways can induce AMPA receptor internalization, NMDA receptor activation enhances AMPA receptor endocytosis via a signaling mechanism required for the induction of LTD.

    View details for Web of Science ID 000167177900015

    View details for PubMedID 11100150

  • Synaptic plasticity and dynamic modulation of the portsynaptic membrane NATURE NEUROSCIENCE Luscher, C., Nicoll, R. A., Malenka, R. C., Muller, D. 2000; 3 (6): 545-550

    Abstract

    The biochemical composition of the postsynaptic membrane and the structure of dendritic spines may be rapidly modulated by synaptic activity. Here we review these findings, discuss their implications for long-term potentiation (LTP) and long-term depression (LTD) and propose a model of sequentially occurring expression mechanisms.

    View details for Web of Science ID 000087249500009

    View details for PubMedID 10816309

  • Distinct roles for ionotropic and metabotropic glutamate receptors in the maturation of excitatory synapses JOURNAL OF NEUROSCIENCE Gomperts, S. N., Carroll, R., Malenka, R. C., Nicoll, R. A. 2000; 20 (6): 2229-2237

    Abstract

    We used the single-cell culture preparation to study the role of activity in the development of glutamatergic synapses in vitro. Rat hippocampal cells grown in isolation on glial islands formed functional autaptic connections and continued to elaborate new synapses throughout the 2 week investigation, resulting in increases in both the evoked AMPA receptor (AMPAR) and NMDA receptor (NMDAR) components of the EPSC. Synaptogenesis was not prevented by chronic blockade of sodium channels or all of the known glutamate receptors. Analysis of miniature EPSCs revealed that AMPAR quantal size doubled over time in vitro whereas NMDAR quantal size remained constant. However, the proportion of synaptic responses mediated only by NMDARs increased over time in vitro. The increase in AMPAR quantal size was prevented by TTX and ionotropic glutamate receptor antagonists, whereas the increase in the proportion of NMDAR-only synapses was prevented by metabotropic glutamate receptor antagonists. Notably, chronic NMDAR blockade incubation did not block the formation of the AMPAR EPSC, indicating that NMDAR-dependent plasticity is not necessary for the onset of AMPAR synaptic transmission in this system. We conclude that action potentials and ionotropic glutamate receptor activation are necessary for the developmental increase in AMPAR quantal size and that metabotropic glutamate receptor activation is required for the production of NMDAR-only synapses, but none of these is essential for synapse formation.

    View details for Web of Science ID 000085724200022

    View details for PubMedID 10704498

  • Dynamin-dependent endocytosis of ionotropic glutamate receptors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Carroll, R. C., Beattie, E. C., Xia, H. H., Luscher, C., Altschuler, Y., Nicoli, R. A., Malenka, R. C., von Zastrow, M. 1999; 96 (24): 14112-14117

    Abstract

    Little is known about the mechanisms that regulate the number of ionotropic glutamate receptors present at excitatory synapses. Herein, we show that GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) are removed from the postsynaptic plasma membrane of cultured hippocampal neurons by rapid, ligand-induced endocytosis. Although endocytosis of AMPARs can be induced by high concentrations of AMPA without concomitant activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs), NMDAR activation is required for detectable endocytosis induced by synaptically released glutamate. Activated AMPARs colocalize with AP2, a marker of endocytic coated pits, and endocytosis of AMPARs is blocked by biochemical inhibition of clathrin-coated pit function or overexpression of a dominant-negative mutant form of dynamin. These results establish that ionotropic receptors are regulated by dynamin-dependent endocytosis and suggest an important role of endocytic membrane trafficking in the postsynaptic modulation of neurotransmission.

    View details for Web of Science ID 000083872900093

    View details for PubMedID 10570207

  • Synaptic plasticity at thalamocortical synapses in developing rat somatosensory cortex: LTP, LTD, and silent synapses JOURNAL OF NEUROBIOLOGY Feldman, D. E., Nicoll, R. A., Malenka, R. C. 1999; 41 (1): 92-101

    Abstract

    Thalamocortical synaptic transmission in the rat's primary somatosensory (S1) cortex is modified by sensory experience during a critical period early in life. Despite the importance of such plasticity for the maturation of thalamocortical circuits, the synaptic basis of this plasticity is unknown. Here, we review evidence suggesting that long-term potentiation and depression (LTP and LTD) of thalamocortical synaptic transmission may be involved in this plasticity. In an in vitro slice preparation, thalamocortical synaptic responses exhibit N-methyl-D-aspartate (NMDA) receptor-dependent LTP and LTD during a developmental period similar to the critical period in vivo. The inability to induce LTP and LTD after the critical period may result in part from a developmental reduction in the duration of NMDA receptor currents. In addition, during the critical period many thalamocortical synapses exhibit NMDA receptor currents but no detectable AMPA receptor currents, and thus may be functionally silent at resting membrane potentials. LTP converts silent synapses to functional ones by causing the rapid appearance of AMPA currents. These observations suggest that thalamocortical synapses may be formed as silent synapses which are subsequently made functional by LTP. LTP and LTD may then regulate the efficacy of these functional synapses and thereby contribute to experience-dependent changes in S1 thalamocortical circuits.

    View details for Web of Science ID 000082951700012

    View details for PubMedID 10504196

  • Long-term potentiation--a decade of progress? Science Malenka, R. C., Nicoll, R. A. 1999; 285 (5435): 1870-1874

    Abstract

    Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.

    View details for PubMedID 10489359

  • Silent glutamatergic synapses in the mammalian brain CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Isaac, J. T., Nicoll, R. A., Malenka, R. C. 1999; 77 (9): 735-737

    Abstract

    Excitatory synaptic transmission in the mammalian brain is mediated primarily by alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors that are thought to be co-localized at individual synapses. However, recent electrophysiological and anatomical data suggest that the synaptic localization of AMPA and NMDA receptors may be independently regulated by neural activity. These data are reviewed here and the implications of these findings for the mechanisms underlying synaptic plasticity are discussed.

    View details for Web of Science ID 000083501200012

    View details for PubMedID 10566951

  • Rabphilin knock-out mice reveal that rabphilin is not required for Rab3 function in regulating neurotransmitter release JOURNAL OF NEUROSCIENCE Schluter, O. M., Schnell, E., Verhage, M., Tzonopoulos, T., Nicoll, R. A., Janz, R., Malenka, R. C., Geppert, M., Sudhof, T. C. 1999; 19 (14): 5834-5846

    Abstract

    Rab3A and rab3C are GTP-binding proteins of synaptic vesicles that regulate vesicle exocytosis. Rabphilin is a candidate rab3 effector at the synapse because it binds to rab3s in a GTP-dependent manner, it is co-localized with rab3s on synaptic vesicles, and it dissociates with rab3s from the vesicles during exocytosis. Rabphilin contains two C(2) domains, which could function as Ca(2+) sensors in exocytosis and is phosphorylated as a function of stimulation. However, it is unknown what essential function, if any, rabphilin performs. One controversial question regards the respective roles of rab3s and rabphilin in localizing each other to synaptic vesicles: although rabphilin is mislocalized in rab3A knock-out mice, purified synaptic vesicles were shown to require rabphilin for binding of rab3A but not rab3A for binding of rabphilin. To test whether rabphilin is involved in localizing rab3s to synaptic vesicles and to explore the functions of rabphilin in regulating exocytosis, we have now analyzed knock-out mice for rabphilin. Mice that lack rabphilin are viable and fertile without obvious physiological impairments. In rabphilin-deficient mice, rab3A is targeted to synaptic vesicles normally, whereas in rab3A-deficient mice, rabphilin transport to synapses is impaired. These results show that rabphilin binds to vesicles via rab3s, consistent with an effector function of rabphilin for a synaptic rab3-signal. Surprisingly, however, no abnormalities in synaptic transmission or plasticity were observed in rabphilin-deficient mice; synaptic properties that are impaired in rab3A knock-out mice were unchanged in rabphilin knock-out mice. Our data thus demonstrate that rabphilin is endowed with the properties of a rab3 effector but is not essential for the regulatory functions of rab3 in synaptic transmission.

    View details for Web of Science ID 000081377600015

    View details for PubMedID 10407024

  • Leaky synapses NEURON Nicoll, R. A., Malenka, R. C. 1999; 23 (2): 197-198

    View details for Web of Science ID 000081218600003

    View details for PubMedID 10399924

  • Lack of AMPA receptor desensitization during basal synaptic transmission in the hippocampal slice JOURNAL OF NEUROPHYSIOLOGY Hjelmstad, G. O., Isaac, J. T., Nicoll, R. A., Malenka, R. C. 1999; 81 (6): 3096-3099

    Abstract

    Excitatory postsynaptic currents in the CA1 region of rat hippocampal slices are mediated primarily by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in response to synaptically released glutamate. Outside-out patches from pyramidal cells in this region have shown that AMPA receptors are desensitized by short (1 ms) pulses of glutamate. We have taken a number of approaches to ask whether synaptic receptors desensitize in response to synaptically released glutamate in the slice. Recordings with paired pulses and minimal stimulation conditions that are presumably activating only a single release site do not show evidence for desensitization. Furthermore, cyclothiazide, a drug that blocks desensitization, does not alter paired-pulse ratios even under conditions of high probability of release, which should maximize desensitization. These results suggest that synaptic receptors do not desensitize in response to synaptically released glutamate during basal synaptic transmission.

    View details for Web of Science ID 000081005800046

    View details for PubMedID 10368425

  • Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area JOURNAL OF NEUROSCIENCE Bonci, A., Malenka, R. C. 1999; 19 (10): 3723-3730

    Abstract

    Excitatory inputs to the ventral tegmental area (VTA) influence the activity of both dopaminergic (DA) and GABAergic (GABA) cells, yet little is known about the basic properties of excitatory synapses on these two cell types. Using a midbrain slice preparation and whole-cell recording techniques, we found that excitatory synapses on DA and GABA cells display several differences. Synapses on DA cells exhibit a depression in response to repetitive activation, are minimally affected by the GABAB receptor agonist baclofen, and express NMDA receptor-dependent long-term potentiation (LTP). In contrast, synapses on GABA cells exhibit a facilitation in response to repetitive activation, are depressed significantly by baclofen, and do not express LTP. The relative contribution of NMDA and non-NMDA receptors to the synaptic currents recorded from the two cell types is the same as is the depression of synaptic transmission elicited by the application of adenosine, serotonin, or methionine enkephalin (met-enkephalin). The significant differences in the manner in which excitatory synaptic inputs to DA and GABA cells in the VTA can be modulated have potentially important implications for understanding the behavior of VTA neurons during normal behavior and during pathological states such as addiction.

    View details for Web of Science ID 000080162400009

    View details for PubMedID 10234004

  • Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures NATURE NEUROSCIENCE Carroll, R. C., Lissin, D. V., von Zastrow, M., Nicoll, R. A., Malenka, R. C. 1999; 2 (5): 454-460

    Abstract

    Synaptic strength can be altered by a variety of pre- or postsynaptic modifications. Here we test the hypothesis that long-term depression (LTD) involves a decrease in the number of glutamate receptors that are clustered at individual synapses in primary cultures of hippocampal neurons. Similar to a prominent form of LTD observed in hippocampal slices, LTD in hippocampal cultures required NMDA receptor activation and was accompanied by a decrease in the amplitude and frequency of miniature excitatory postsynaptic currents. Immunocytochemical analysis revealed that induction of LTD caused a concurrent decrease in the number of AMPA receptors clustered at synapses but had no effect on synaptic NMDA receptor clusters. These results suggest that a subtype-specific redistribution of synaptic glutamate receptors contributes to NMDA receptor-dependent LTD.

    View details for Web of Science ID 000084609400016

    View details for PubMedID 10321250

  • Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hsia, A. Y., Masliah, E., MCCONLOGUE, L., Yu, G. Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R. C., Nicoll, R. A., Mucke, L. 1999; 96 (6): 3228-3233

    Abstract

    Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, Abeta42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Abeta peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Abeta production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Abeta that is independent of plaque formation.

    View details for Web of Science ID 000079224500120

    View details for PubMedID 10077666

  • Rapid, activation-induced redistribution of ionotropic glutamate receptors in cultured hippocampal neurons JOURNAL OF NEUROSCIENCE Lissin, D. V., Carroll, R. C., Nicoll, R. A., Malenka, R. C., von Zastrow, M. 1999; 19 (4): 1263-1272

    Abstract

    We have examined the membrane localization of an AMPA receptor subunit (GluR1) and an NMDA receptor subunit (NR1) endogenously expressed in primary cultures of rat hippocampal neurons. In unstimulated cultures, both GluR1 and NR1 subunits were concentrated in SV2-positive synaptic clusters associated with dendritic shafts and spines. Within 5 min after the addition of 100 microM glutamate to the culture medium, a rapid and selective redistribution of GluR1 subunits away from a subset of synaptic sites was observed. This redistribution of GluR1 subunits was also induced by AMPA, did not require NMDA receptor activation, did not result from ligand-induced neurotoxicity, and was reversible after the removal of agonist. The activation-induced redistribution of GluR1 subunits was associated with a pronounced (approximately 50%) decrease in the frequency of miniature EPSCs, consistent with a role of GluR1 subunit redistribution in mediating rapid regulation of synaptic efficacy. We conclude that ionotropic glutamate receptors are regulated in native neurons by rapid, subtype-specific membrane trafficking, which may modulate synaptic transmission in response to physiological or pathophysiological activation.

    View details for Web of Science ID 000078603500010

    View details for PubMedID 9952404

  • Hippocampal long-term potentiation preserves the fidelity of postsynaptic responses to presynaptic bursts JOURNAL OF NEUROSCIENCE Selig, D. K., Nicoll, R. A., Malenka, R. C. 1999; 19 (4): 1236-1246

    Abstract

    Hippocampal cells often fire prolonged bursts of action potentials, resulting in dynamic modulation of postsynaptic responses; yet long-term potentiation (LTP) has routinely been studied using only single presynaptic stimuli given at low frequency. Recent work on neocortical synapses has suggested that LTP may cause a "redistribution of synaptic strength" in which synaptic responses to the first stimulus of a presynaptic burst of action potentials are potentiated with later responses depressed. We have examined whether this redistribution occurs at hippocampal synapses during LTP. Using prolonged bursts that result in maximal short-term depression of later responses within the burst, we found that LTP resulted in a uniform potentiation of individual responses throughout the burst rather than a redistribution of synaptic strength. This occurred both at Schaffer collateral-CA1 synapses and at CA3-CA3 synapses, the latter being activated and monitored using paired recordings. Thus in the hippocampus, LTP preserves the fidelity of postsynaptic responses to presynaptic bursts by a uniform increase rather than a redistribution of synaptic strength, a finding that suggests there are important differences between neocortex and hippocampus in how long-term changes in synaptic strength are used to encode new information.

    View details for Web of Science ID 000078603500007

    View details for PubMedID 9952401

  • An immunocytochemical assay for activity-dependent redistribution of glutamate receptors from the postsynaptic plasma membrane MOLECULAR AND FUNCTIONAL DIVERSITY OF ION CHANNELS AND RECEPTORS Lissin, D. V., Malenka, R. C., von Zastrow, M. 1999; 868: 550-553

    View details for Web of Science ID 000081584300058

    View details for PubMedID 10414334

  • Expression mechanisms underlying NMDA receptor-dependent long-term potentiation MOLECULAR AND FUNCTIONAL DIVERSITY OF ION CHANNELS AND RECEPTORS Nicoll, R. A., Malenka, R. C. 1999; 868: 515-525

    Abstract

    Long-term potentiation (LTP) is currently the best available cellular model for learning and memory in the mammalian brain. In the CA1 region of the hippocampus, as well as in many other areas of the CNS, its induction requires a rise in postsynaptic Ca2+ via activation of NMDA receptors. What happens after the rise in postsynaptic Ca2+ is less clear. This paper summarizes experiments performed over the last decade in slice preparations that address the site of expression of LTP. While a large number of laboratories have contributed importantly to this issue, this review will rely primarily on experiments performed in the authors' laboratory. The experiments to be discussed can be broadly divided into two groups: those designed to determine if an increase in glutamate release occurs during LTP and those designed to determine if a change in postsynaptic sensitivity to glutamate occurs during LTP. Experiments in the first category include the analysis of dual-component excitatory postsynaptic currents (EPSCs), paired-pulse facilitation, saturating release probability, the use of MK-801 to measure release probability, and glial glutamate transporter currents to measure directly the synaptic release of glutamate. Experiments in the second category include analysis of miniature EPSC amplitudes, measurements of synaptic potency, the consequences of loading cells with the constitutively activated form of CaM kinase II, and the evidence that during LTP postsynaptically silent synapses become functional. We will argue that, while numerous experiments fail to support a presynaptic expression mechanism, many experiments do point to a postsynaptic expression mechanism. The decrease in synaptic failures during LTP, the only generally accepted experimental result that supports a presynaptic expression mechanism, can be explained by postsynaptically silent synapses. Future directions for research in this field include activity-dependent targeting of glutamate receptors and the functional consequences of phosphorylation of AMPA receptors.

    View details for Web of Science ID 000081584300052

    View details for PubMedID 10414328

  • Postsynaptically silent synapses in single neuron cultures NEURON Gomperts, S. N., Rao, A., Craig, A. M., Malenka, R. C., Nicoll, R. A. 1998; 21 (6): 1443-1451

    Abstract

    We have used the synapses that isolated hippocampal cells in culture form onto themselves (autapses) to determine if some synapses lack functional AMPA receptors (AMPARs). A comparison of the synaptic variability of the AMPAR- and NMDAR-mediated evoked responses, as well as of miniature synaptic responses, indicates that a population of events exists that only contains an NMDAR component. Spillover of glutamate from adjacent synapses cannot explain these results because in single cell cultures all synaptic events mediated by AMPARs should be detected. Immunocytochemical analysis of these cultures clearly reveals a population of synapses with puncta for NR1 (NMDAR) but not for GluR1 (AMPAR). These results provide strong anatomical and physiological evidence for the existence of postsynaptically silent synapses.

    View details for Web of Science ID 000077910600025

    View details for PubMedID 9883736

  • Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus JOURNAL OF NEUROPHYSIOLOGY Frerking, M., Malenka, R. C., Nicoll, R. A. 1998; 80 (6): 3383-3386

    Abstract

    Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. J. Neurophysiol. 80: 3383-3386, 1998. Brain-derived neurotrophic factor (BDNF) has been reported to have rapid effects on synaptic transmission in the hippocampus. We report here that bath application of BDNF causes a small but significant decrease in stimulus-evoked inhibitory postsynaptic currents (IPSCs) on CA1 pyramidal cells, which is prevented by the tyrosine kinase inhibitor lavendustin A. BDNF causes a decrease in the 1/CV2 of the IPSC, and also reduces paired-pulse depression of the IPSC, suggesting a presynaptic site of action. In contrast, BDNF did not have a detectable effect on field excitatory postsynaptic potentials measured in stratum radiatum. We conclude that BDNF has a selective depressant action on inhibitory transmission in the hippocampus, due at least in part to a presynaptic mechanism.

    View details for Web of Science ID 000077835000054

    View details for PubMedID 9862938

  • Effects of PKA and PKC on miniature excitatory postsynaptic currents in CA1 pyramidal cells JOURNAL OF NEUROPHYSIOLOGY Carroll, R. C., Nicoll, R. A., Malenka, R. C. 1998; 80 (5): 2797-2800

    Abstract

    Protein kinases play an important role in controlling synaptic strength at excitatory synapses on CA1 pyramidal cells. We examined the effects of activating cAMP-dependent protein kinase or protein kinase C (PKC) on the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) with perforated patch recording techniques. Both forskolin and phorbol-12,13-dibutryate (PDBu) caused a large increase in mEPSC frequency, but only PDBu increased mEPSC amplitude, an effect that was not observed when standard whole cell recording was performed. These results support biochemical observations indicating that PKC, similar to calcium/calmodulin-dependent protein kinase II, has an important role in controlling synaptic strength via modulation of AMPA receptor function, potentially through the direct phosphorylation of the GluR1 subunit.

    View details for Web of Science ID 000077069000047

    View details for PubMedID 9819284

  • Synaptic activation of kainate receptors on hippocampal interneurons NATURE NEUROSCIENCE Frerking, M., Malenka, R. C., Nicoll, R. A. 1998; 1 (6): 479-486

    Abstract

    Although kainate receptor activation has been known to evoke epileptiform activity, little is known about the role of kainate receptors in synaptic transmission. Here we report that kainate (KA) receptors are present on interneurons and, when activated, cause a large increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) driven by action potentials. Stimulation of excitatory afferents generates a pharmacologically identifiable synaptic current mediated by KA receptors in interneurons. This synaptic current is similar to that mediated by AMPA receptors in its response to short stimulus trains, current-voltage relations and coefficient of variation, but it is much smaller in peak amplitude and much slower. KA application also considerably depresses evoked IPSCs. This depression seems to be in large part an indirect consequence of the repetitive firing evoked by the activation of the interneuronal somatic/dendritic KA receptors.

    View details for Web of Science ID 000076406900012

    View details for PubMedID 10196545

  • A role for cAMP in long-term depression at hippocampal mossy fiber synapses NEURON Tzounopoulos, T., Janz, R., Sudhof, T. C., Nicoll, R. A., Malenka, R. C. 1998; 21 (4): 837-845

    Abstract

    Mossy fiber synapses on hippocampal CA3 pyramidal cells, in addition to expressing an NMDA receptor-independent form of long-term potentiation (LTP), have recently been shown to express a novel presynaptic form of long-term depression (LTD). We have studied the mechanisms underlying mossy fiber LTD and present evidence that it is triggered, at least in part, by a metabotropic glutamate receptor-mediated decrease in adenylyl cyclase activity, which leads to a decrease in the activity of the cAMP-dependent protein kinase (PKA) and a reversal of the presynaptic processes responsible for mossy fiber LTP. The bidirectional control of synaptic strength at mossy fiber synapses by activity therefore appears to be due to modulation of the cAMP-PKA signaling pathway in mossy fiber boutons.

    View details for Web of Science ID 000076697300026

    View details for PubMedID 9808469

  • Monitoring glutamate release during LTP with glial transporter currents NEURON Luscher, C., Malenka, R. C., Nicoll, R. A. 1998; 21 (2): 435-441

    Abstract

    Although much has been learned about the mechanisms underlying NMDA receptor-dependent long-term potentiation (LTP), considerable debate remains as to whether LTP is expressed as an increase in the synaptic release of glutamate or as an increase in the sensitivity of the postsynaptic glutamate receptors. We have directly measured changes in the synaptic release of glutamate by recording synaptically evoked glial glutamate transporter currents with whole-cell recording. Glial cell responses were very sensitive to manipulations known to change the release of glutamate yet remained constant during LTP. These results argue strongly for a postsynaptic expression mechanism for LTP.

    View details for Web of Science ID 000075598300020

    View details for PubMedID 9728924

  • Long-term depression at thalamocortical synapses in developing rat somatosensory cortex NEURON Feldman, D. E., Nicoll, R. A., Malenka, R. C., Isaac, J. T. 1998; 21 (2): 347-357

    Abstract

    Sensory experience during an early critical period guides the development of thalamocortical circuits in many cortical areas. This process has been hypothesized to involve long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical synapses. Here, we show that thalamocortical synapses in rat barrel cortex can express LTD, and that LTD is most readily induced during a developmental period that is similar to the critical period for thalamocortical plasticity in vivo. Thalamocortical LTD is homosynaptic and dependent on activation of N-methyl-D-aspartate (NMDA) receptors. The age-related decline of LTD is not due to changes in inhibition nor to changes in NMDA receptor voltage dependence. Minimal stimulation experiments indicate that, unlike thalamocortical LTP, thalamocortical LTD is not associated with a significant change in failure rate. The existence of LTD and its developmental time course suggest that LTD, like LTP, may contribute to the refinement of thalamocortical inputs in vivo.

    View details for Web of Science ID 000075598300012

    View details for PubMedID 9728916

  • A tale of two transmitters. Science Nicoll, R. A., Malenka, R. C. 1998; 281 (5375): 360-361

    View details for PubMedID 9705712

  • NMDA receptor-dependent and metabotropic glutamate receptor-dependent forms of long-term depression coexist in CA1 hippocampal pyramidal cells NEUROBIOLOGY OF LEARNING AND MEMORY Nicoll, R. A., Oliet, S. H., Malenka, R. C. 1998; 70 (1-2): 62-72

    Abstract

    We have found that two distinct forms of long-term depression (LTD), one dependent on the activation of NMDA receptors (NMDARs) and the other dependent on the activation of metabotropic glutamate receptors (mGluRs), coexist in pyramidal cells of the CA1 region of the hippocampus of juvenile rats (11-35 days). Both forms were pathway specific, required membrane depolarization, and were blocked by chelating postsynaptic Ca2+ with BAPTA. The mGluR-LTD, but not the NMDAR-LTD, was blocked by the T-type Ca2+ channel blocker Ni2+ and intracellular administration of a protein kinase C inhibitory peptide. In contrast, the protein phosphatase inhibitor Microcystin LR blocked NMDAR-LTD, but not mGluR-LTD. NMDAR-LTD is associated with a decrease in the size of quantal excitatory postsynaptic currents, whereas for mGluR-LTD there was no change in quantal size, but a large decrease in the frequency of events. While mGluR-LTD did not interact with NMDAR-dependent long term potentiation (LTP), NMDAR-LTD was capable of reversing LTP. Prior saturation of mGluR-LTD had no effect on NMDAR-LTD. NMDAR-LTD and mGluR-LTD thus appear to be mechanistically distinct forms of synaptic plasticity in that they share neither induction nor expression mechanisms.

    View details for Web of Science ID 000076440800006

    View details for PubMedID 9753587

  • Activity differentially regulates the surface expression of synaptic AMPA and NMDA glutamate receptors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lissin, D. V., Gomperts, S. N., Carroll, R. C., Christine, C. W., Kalman, D., Kitamura, M., Hardy, S., Nicoll, R. A., Malenka, R. C., von Zastrow, M. 1998; 95 (12): 7097-7102

    Abstract

    Distinct subtypes of glutamate receptors often are colocalized at individual excitatory synapses in the mammalian brain yet appear to subserve distinct functions. To address whether neuronal activity may differentially regulate the surface expression at synapses of two specific subtypes of ionotropic glutamate receptors we epitope-tagged an AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit (GluR1) and an NMDA (N-methyl-D-aspartate) receptor subunit (NR1) on their extracellular termini and expressed these proteins in cultured hippocampal neurons using recombinant adenoviruses. Both receptor subtypes were appropriately targeted to the synaptic plasma membrane as defined by colocalization with the synaptic vesicle protein synaptophysin. Increasing activity in the network of cultured cells by prolonged blockade of inhibitory synapses with the gamma-aminobutyric acid type A receptor antagonist picrotoxin caused an activity-dependent and NMDA receptor-dependent decrease in surface expression of GluR1, but not NR1, at synapses. Consistent with this observation identical treatment of noninfected cultures decreased the contribution of endogenous AMPA receptors to synaptic currents relative to endogenous NMDA receptors. These results indicate that neuronal activity can differentially regulate the surface expression of AMPA and NMDA receptors at individual synapses.

    View details for Web of Science ID 000074131900095

    View details for PubMedID 9618545

  • Long-term depression with a flash NATURE NEUROSCIENCE Malenka, R. C., Nicoll, R. A. 1998; 1 (2): 89-90

    View details for Web of Science ID 000076361100003

    View details for PubMedID 10195117

  • All-or-none potentiation at CA3-CA1 synapses PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Petersen, C. C., Malenka, R. C., Nicoll, R. A., Hopfield, J. J. 1998; 95 (8): 4732-4737

    Abstract

    The molecular mechanisms underlying long-term potentiation in the hippocampus have received much attention because of the likely functional importance of synaptic plasticity for information storage and the development of neuronal connectivity. Surprisingly, it remains unclear whether activity modifies the strength of individual synapses in a digital (all-or-none) or analog (graded) manner. Here we characterize step-like all-or-none transitions from baseline synaptic transmission to potentiated states following protocols for inducing potentiation at putative single CA3-CA1 synaptic connections. Individual synapses appear to have all-or-none potentiation indicative of highly cooperative processes but different thresholds for undergoing potentiation. These results raise the possibility that some forms of synaptic memory may be stored in a digital manner in the brain.

    View details for Web of Science ID 000073120800119

    View details for PubMedID 9539807

  • Development of excitatory circuitry in the hippocampus JOURNAL OF NEUROPHYSIOLOGY Hsia, A. Y., Malenka, R. C., Nicoll, R. A. 1998; 79 (4): 2013-2024

    Abstract

    Assessing the development of local circuitry in the hippocampus has relied primarily on anatomic studies. Here we take a physiological approach, to directly evaluate the means by which the mature state of connectivity between CA3 and CA1 hippocampal pyramidal cells is established. Using a technique of comparing miniature excitatory postsynaptic currents (mEPSCs) to EPSCs in response to spontaneously occurring action potentials in CA3 cells, we found that from neonatal to adult ages, functional synapses are created and serve to increase the degree of connectivity between CA3-CA1 cell pairs. Neither the probability of release nor mean quantal size was found to change significantly with age. However, the variability of quantal events decreases substantially as synapses mature. Thus in the hippocampus the developmental strategy for enhancing excitatory synaptic transmission does not appear to involve an increase in the efficacy at individual synapses, but rather an increase in the connectivity between cell pairs.

    View details for Web of Science ID 000073273700036

    View details for PubMedID 9535965

  • Postsynaptic membrane fusion and long-term potentiation SCIENCE Lledo, P. M., Zhang, X. Y., Sudhof, T. C., Malenka, R. C., Nicoll, R. A. 1998; 279 (5349): 399-403

    Abstract

    The possibility that membrane fusion events in the postsynaptic cell may be required for the change in synaptic strength resulting from long-term potentiation (LTP) was examined. Introducing substances into the postsynaptic cell that block membrane fusion at a number of different steps reduced LTP. Introducing SNAP, a protein that promotes membrane fusion, into cells enhanced synaptic transmission, and this enhancement was significantly less when generated in synapses that expressed LTP. Thus, postsynaptic fusion events, which could be involved either in retrograde signaling or in regulating postsynaptic receptor function or both, contribute to LTP.

    View details for Web of Science ID 000071570800051

    View details for PubMedID 9430593

  • Synaptic refractory period provides a measure of probability of release in the hippocampus NEURON Hjelmstad, G. O., Nicoll, R. A., Malenka, R. C. 1997; 19 (6): 1309-1318

    Abstract

    Despite extensive research, much controversy remains regarding the locus of expression of long-term potentiation (LTP) in area CA1 of the hippocampus, specifically, whether LTP is accompanied by an increase in the probability of release (p(r)) of synaptic vesicles. We have developed a novel method for assaying p(r), which utilizes the synaptic refractory period--a brief 5-6 ms period following release during which the synapse is incapable of transmission (Stevens and Wang, 1995). We show that this assay is sensitive to a battery of manipulations that affect p(r) but find no change following either NMDA receptor-dependent LTP or long-term depression (LTD).

    View details for Web of Science ID 000071236500017

    View details for PubMedID 9427253

  • Silent synapses speak up NEURON Malenka, R. C., Nicoll, R. A. 1997; 19 (3): 473-476

    View details for Web of Science ID A1997XZ01600002

    View details for PubMedID 9331339

  • G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons NEURON Luscher, C., Jan, L. Y., Stoffel, M., Malenka, R. C., Nicoll, R. A. 1997; 19 (3): 687-695

    Abstract

    To study the role of G protein-coupled, inwardly rectifying K+ (GIRK) channels in mediating neurotransmitter actions in hippocampal neurons, we have examined slices from transgenic mice lacking the GIRK2 gene. The outward currents evoked by agonists for GABA(B) receptors, 5HT1A receptors, and adenosine A1 receptors were essentially absent in mutant mice, while the inward current evoked by muscarinic receptor activation was unaltered. In contrast, the presynaptic inhibitory action of a number of presynaptic receptors on excitatory and inhibitory terminals was unaltered in mutant mice. These included GABA(B), adenosine, muscarinic, metabotropic glutamate, and NPY receptors on excitatory synapses and GABA(B) and opioid receptors on inhibitory synapses. These findings suggest that a number of G protein-coupled receptors activate the same class of postsynaptic K+ channel, which contains GIRK2. In addition, the GIRK2 channels play no role in the inhibition mediated by presynaptic G protein-coupled receptors, suggesting that the same receptor can couple to different effector systems according to its subcellular location in the neuron.

    View details for Web of Science ID A1997XZ01600021

    View details for PubMedID 9331358

  • Rab3A is essential for mossy fibre long-term potentiation in the hippocampus NATURE Castillo, P. E., Janz, R., Sudhof, T. C., Tzounopoulos, T., Malenka, R. C., Nicoll, R. A. 1997; 388 (6642): 590-593

    Abstract

    Repetitive activation of excitatory synapses in the central nervous system results in a long-lasting increase in synaptic transmission called long-term potentiation (LTP). It is generally believed that this synaptic plasticity may underlie certain forms of learning and memory. LTP at most synapses involves the activation of the NMDA (N-methyl-D-aspartate) subtype of glutamate receptor, but LTP at hippocampal mossy fibre synapses is independent of NMDA receptors and has a component that is induced and expressed presynaptically. It appears to be triggered by a rise in presynaptic Ca2+, and requires the activation of protein kinase A, which leads to an increased release of glutamate. A great deal is known about the biochemical steps involved in the vesicular release of transmitter, but none of these steps has been directly implicated in long-term synaptic plasticity. Here we show that, although a variety of short-term plasticities are normal, LTP at mossy fibre synapses is abolished in mice lacking the synaptic vesicle protein Rab3A.

    View details for Web of Science ID A1997XP72200051

    View details for PubMedID 9252190

  • Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons NATURE Castillo, P. E., Malenka, R. C., Nicoll, R. A. 1997; 388 (6638): 182-186

    Abstract

    Glutamate, the neurotransmitter at most excitatory synapses in the brain, activates a variety of receptor subtypes that can broadly be divided into ionotropic (ligand-gated ion channels) and metabotropic (G-protein-coupled) receptors. Ionotropic receptors mediate fast excitatory synaptic transmission, and based on pharmacological and molecular biological studies are divided into NMDA and non-NMDA subtypes. The non-NMDA receptor group is further divided into AMPA and kainate subtypes. Virtually all fast excitatory postsynaptic currents studied so far in the central nervous system are mediated by the AMPA and NMDA subtypes of receptors. Surprisingly, despite extensive analysis of their structure, biophysical properties and anatomical distribution, a synaptic role for kainate receptors in the brain has not been found. Here we report that repetitive activation of the hippocampal mossy fibre pathway, which is associated with high-affinity kainate binding and many of the kainate receptor subtypes, generates a slow excitatory synaptic current with all of the properties expected of a kainate receptor. This activity-dependent synaptic current greatly augments the excitatory drive of CA3 pyramidal cells.

    View details for Web of Science ID A1997XK10900052

    View details for PubMedID 9217159

  • Learning mechanisms: the case for CaM-KII. Science Lisman, J., Malenka, R. C., Nicoll, R. A., Malinow, R. 1997; 276 (5321): 2001-2002

    View details for PubMedID 9221509

  • Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells NEURON Oliet, S. H., Malenka, R. C., Nicoll, R. A. 1997; 18 (6): 969-982

    Abstract

    Two distinct forms of long-term depression (LTD), one dependent on the activation of NMDA receptors (NMDARs) and the other dependent on the activation of metabotropic glutamate receptors (mGluRs), are shown to coexist in CA1 hippocampal pyramidal cells of juvenile (11-35 day-old) rats. Both forms were pathway specific and required membrane depolarization and a rise in postsynaptic Ca2+. mGluR-LTD, but not NMDAR-LTD, required the activation of T-type Ca2+ channels, group 1 mGluRs, and protein kinase C, while NMDAR-LTD, but not mGluR-LTD, required protein phosphatase activity. NMDAR-LTD was associated with a decrease in the size of quantal excitatory postsynaptic currents, whereas for mGluR-LTD there was no change in quantal size, but a large decrease in the frequency of events. NMDAR-LTD, but not mGluR-LTD, reversed NMDAR-dependent long-term potentiation, and NMDAR-LTD was unaffected by prior saturation of mGluR-LTD. These findings indicate that NMDAR-LTD and mGluR-LTD are mechanistically distinct forms of synaptic plasticity.

    View details for Web of Science ID A1997XJ10200015

    View details for PubMedID 9208864

  • Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors NATURE Scanziani, M., Salin, P. A., Vogt, K. E., Malenka, R. C., Nicoll, R. A. 1997; 385 (6617): 630-634

    Abstract

    The classical view of fast chemical synaptic transmission is that released neurotransmitter acts locally on postsynaptic receptors and is cleared from the synaptic cleft within a few milliseconds by diffusion and by specific reuptake mechanisms. This rapid clearance restricts the spread of neurotransmitter and, combined with the low affinities of many ionotropic receptors, ensures that synaptic transmission occurs in a point-to-point fashion. We now show, however, that when transmitter release is enhanced at hippocampal mossy fibre synapses, the concentration of glutamate increases and its clearance is delayed; this allows it to spread away from the synapse and to activate presynaptic inhibitory metabotropic glutamate receptors (mGluRs). At normal levels of glutamate release during low-frequency activity, these presynaptic receptors are not activated. When glutamate concentration is increased by higher-frequency activity or by blocking glutamate uptake, however, these receptors become activated, leading to a rapid inhibition of transmitter release. This effect may be related to the long-term depression of mossy fibre synaptic responses that has recently been shown after prolonged activation of presynaptic mGluRs (refs 2, 3). The use-dependent activation of presynaptic mGluRs that we describe here thus represents a negative feedback mechanism for controlling the strength of synaptic transmission.

    View details for Web of Science ID A1997WH29400049

    View details for PubMedID 9024660

  • Silent synapses during development of thalamocortical inputs NEURON Isaac, J. T., Crair, M. C., Nicoll, R. A., Malenka, R. C. 1997; 18 (2): 269-280

    Abstract

    During development, activity-dependent mechanisms are thought to contribute to the refinement of topographical projections from the thalamus to the cortex. Because activity-dependent increases in synaptic strength may contribute to the stabilization of synaptic connections, we have explored the mechanisms of long-term potentiation (LTP) at thalamocortical synapses in rat somatosensory (barrel) cortex. During early postnatal development (postnatal days 2-5), we find that a significant proportion of thalamocortical synapses are functionally silent and that these are converted to functional synapses during LTP. Silent synapses disappear by postnatal day 8-9, the exact time at which the susceptibility of these synapses to LTP is lost. These findings suggest that the activity-dependent conversion of silent to functional synapses due to correlated pre- and postsynaptic activity may contribute to the early development and refinement of thalamocortical inputs to cortex.

    View details for Web of Science ID A1997WK82200010

    View details for PubMedID 9052797

  • Distinct short-term plasticity at two excitatory synapses in the hippocampus PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Salin, P. A., Scanziani, M., Malenka, R. C., Nicoll, R. A. 1996; 93 (23): 13304-13309

    Abstract

    A single mossy fiber input contains several release sites and is located on the proximal portion of the apical dendrite of CA3 neurons. It is, therefore, well suited to exert a strong influence on pyramidal cell excitability. Accordingly, the mossy fiber synapse has been referred to as a detonator or teacher synapse in autoassociative network models of the hippocampus. The very low firing rates of granule cells [Jung, M. W. & McNaughton, B. L. (1993) Hippocampus 3, 165-182], which give rise to the mossy fibers, raise the question of how the mossy fiber synapse temporally integrates synaptic activity. We have therefore addressed the frequency dependence of mossy fiber transmission and compared it to associational/commissural synapses in the CA3 region of the hippocampus. Paired pulse facilitation had a similar time course, but was 2-fold greater for mossy fiber synapses. Frequency facilitation, during which repetitive stimulation causes a reversible growth in synaptic transmission, was markedly different at the two synapses. At associational/ commissural synapses facilitation occurred only at frequencies greater than once every 10 s and reached a magnitude of about 125% of control. At mossy fiber synapses, facilitation occurred at frequencies as low as once every 40 s and reached a magnitude of 6-fold. Frequency facilitation was dependent on a rise in intraterminal Ca2+ and activation of Ca2+/calmodulin-dependent kinase II, and was greatly reduced at synapses expressing mossy fiber long-term potentiation. These results indicate that the mossy fiber synapse is able to integrate granule cell spiking activity over a broad range of frequencies, and this dynamic range is substantially reduced by long-term potentiation.

    View details for Web of Science ID A1996VT05400113

    View details for PubMedID 8917586

  • Long-term potentiation at single fiber inputs to hippocampal CA1 pyramidal cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Isaac, J. T., Hjelmstad, G. O., Nicoll, R. A., Malenka, R. C. 1996; 93 (16): 8710-8715

    Abstract

    Despite extensive investigation, it remains unclear whether presynaptic and/or postsynaptic modifications are primarily responsible for the expression of long-term potentiation (LTP) in the CA1 region of the hippocampus. Here we address this issue by using techniques that maximize the likelihood of stimulating a single axon and thereby presumably a single synapse before and after the induction of LTP. Several basic properties of synaptic transmission were examined including the probability of neurotransmitter release (Pr), the quantal size (q), and the so-called potency, which is defined as the average size of the synaptic response when release of transmitter does occur. LTP was routinely associated with an increase in potency, whereas increases in Pr alone were not observed. LTP was also reliably induced when baseline Pr was high, indicating that synapses with high Pr can express LTP. These results suggest that the mechanism for the expression of LTP involves an increase in q and is difficult to explain by an increase in Pr alone.

    View details for Web of Science ID A1996VB32500101

    View details for PubMedID 8710936

  • Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus LEARNING & MEMORY Selig, D. K., Segal, M. R., Liao, D., Malenka, R. C., Malinow, R., Nicoll, R. A., Lisman, J. E. 1996; 3 (1): 42-48

    Abstract

    The mechanisms underlying the generation of NMDA receptor-dependent LTP in the CA1 region of the hippocampus continue to receive a great deal of attention because of the postulated importance of LTP as a synaptic mechanism for learning and memory. It is well accepted that the initial induction of LTP occurs in the postsynaptic cell, but the site of expression remains controversial. One prominent hypothesis is that LTP involves the release of one or more retrograde messengers that act on the presynaptic terminal to enhance transmitter release. Recently, evidence has been presented that retrograde messengers function to activate presynaptic guanylyl cyclase and that the resulting rise in presynaptic cGMP levels, when accompanied by presynaptic activity, is responsible for generating an early component of LTP. We have tested this hypothesis by examining whether synaptic strength is increased by coupling tetanic stimulation with application of a membrane-permeable analog of cGMP. The experiments were done in the presence of an NMDA receptor antagonist to block postsynaptic induction mechanisms. Under a variety of experimental conditions, this manipulation failed to generate LTP, suggesting that an increase in cGMP levels accompanied by presynaptic activity is not sufficient to generate LTP in the CA1 region of the hippocampus.

    View details for Web of Science ID A1996VG62900004

    View details for PubMedID 10456075

  • Long-term potentiation in cultures of single hippocampal granule cells: A presynaptic form of plasticity NEURON Tong, G., Malenka, R. C., Nicoll, R. A. 1996; 16 (6): 1147-1157

    Abstract

    We have explored the mechanisms of mossy fiber long-term potentiation (LTP) at autapses in single-cell cultures of guinea pig hippocampal dentate granule cells. L-AP4-sensitive, but not insensitive, cells responded to a brief tetanus with a sustained potentiation in the synaptic responses. The induction of this LTP appeared identical to that observed in hippocampal mossy fiber synapses in situ, in that it required a rise in presynaptic Ca2+ and activation of protein kinase A. Its expression also appeared to be presynaptic and was due, at least in part, to events that occurred after the entry of Ca2+ and to the switching on of previously silent release sites.

    View details for Web of Science ID A1996UU11800012

    View details for PubMedID 8663991

  • Role of intercellular interactions in heterosynaptic long-term depression NATURE Scanziani, M., Malenka, R. C., Nicoll, R. A. 1996; 380 (6573): 446-450

    Abstract

    Bidirectional control of synaptic strength is thought to be important for the development of neuronal circuits and information storage. The demonstration of homosynaptic long-term depression greatly enhances the usefulness of the synapse as a mnemonic device, but theoreticians have also seen the need for heterosynaptic decreases in synaptic efficacy, both in neuronal development and information storage. Indeed, induction of long-term potentiation in one population of synapses can be associated with a modest depression at neighbouring inactive synapses in the same population of cells. Here we report that in the CA1 region of the hippocampus this heterosynaptic long-term depression has the property that its sites of induction and expression occur in different populations of cells and thus requires the spread of a signal between neurons. Such a mechanism ensures a widespread distribution of this form of plasticity.

    View details for Web of Science ID A1996UD59000064

    View details for PubMedID 8602244

  • Expression mechanisms of long-term potentiation in the hippocampus JOURNAL OF PHYSIOLOGY-PARIS Isaac, J. T., Oliet, S. H., Hjelmstad, G. O., Nicoll, R. A., Malenka, R. C. 1996; 90 (5-6): 299-303

    Abstract

    We have taken a number of different experimental approaches to address whether long-term potentiation (LTP) in hippocampal CA1 pyramidal cells is due primarily to presynaptic or postsynaptic modifications. Examination of miniature EPSCs or EPSCs evoked using minimal stimulation indicate that quantal size increasing during LTP. The conversion of silent to functional synapses may contribute to the LTP-induced changes in mEPSC frequency and failure rate that previously have been attributed to an increase in the probability if transmitter release.

    View details for Web of Science ID A1996WQ67500002

    View details for PubMedID 9089495

  • LONG-TERM POTENTIATION IN MICE LACKING SYNAPSINS NEUROPHARMACOLOGY SPILLANE, D. M., Rosahl, T. W., Sudhof, T. C., Malenka, R. C. 1995; 34 (11): 1573-1579

    Abstract

    Synapsin I and synapsin II are widely expressed synaptic vesicle phosphoproteins that have been proposed to play an important role in synaptic transmission and synaptic plasticity. To gain further insight into the functional significance of the phosphorylation sites on the synapsins, we have examined a number of synaptic processes thought to be mediated by protein kinases in knockout mice lacking both forms of synapsin (Rosahl et al., 1995). Long-term potentiation (LTP) at both the mossy fiber (MF)-CA3 pyramidal cell synapse and the Schaffer collateral-CA1 pyramidal cell synapse appears normal in hippocampal slices prepared from mice lacking synapsins. Moreover, the effects on synaptic transmission of forskolin at MF synapses and H-7 at synapses on CA1 cells are also normal in the mutant mice. These results indicate that the synapsins are not necessary for: (1) the induction or expression of two different forms of LTP in the hippocampus, (2) the enhancement in transmitter release elicited by activation of the cAMP-dependent protein kinase (PKA) and (3) the depression of synaptic transmission caused by H-7. Although disappointing, these results are important in that they exclude the most abundant family of synaptic phosphoproteins as an essential component of long-term synaptic plasticity.

    View details for Web of Science ID A1995TD88400024

    View details for PubMedID 8606805

  • ESSENTIAL FUNCTIONS OF SYNAPSIN-I AND SYNAPSIN-II IN SYNAPTIC VESICLE REGULATION NATURE Rosahl, T. W., Spillane, D., Missler, M., Herz, J., Selig, D. K., Wolff, J. R., Hammer, R. E., Malenka, R. C., Sudhof, T. C. 1995; 375 (6531): 488-493

    Abstract

    Synaptic vesicles are coated by synapsins, phosphoproteins that account for 9% of the vesicle protein. To analyse the functions of these proteins, we have studied knockout mice lacking either synapsin I, synapsin II, or both. Mice lacking synapsins are viable and fertile with no gross anatomical abnormalities, but experience seizures with a frequency proportional to the number of mutant alleles. Synapsin-II and double knockouts, but not synapsin-I knockouts, exhibit decreased post-tetanic potentiation and severe synaptic depression upon repetitive stimulation. Intrinsic synaptic-vesicle membrane proteins, but not peripheral membrane proteins or other synaptic proteins, are slightly decreased in individual knockouts and more severely reduced in double knockouts, as is the number of synaptic vesicles. Thus synapsins are not required for neurite outgrowth, synaptogenesis or the basic mechanics of synaptic vesicle traffic, but are essential for accelerating this traffic during repetitive stimulation. The phenotype of the synapsin knockouts could be explained either by deficient recruitment of synaptic vesicles to the active zone, or by impaired maturation of vesicles at the active zone, both of which could lead to a secondary destabilization of synaptic vesicles.

    View details for Web of Science ID A1995RC18800048

    View details for PubMedID 7777057

  • SHORT-TERM SYNAPTIC PLASTICITY IS ALTERED IN MICE LACKING SYNAPSIN-I CELL Rosahl, T. W., Geppert, M., Spillane, D., Herz, J., Hammer, R. E., Malenka, R. C., Sudhof, T. C. 1993; 75 (4): 661-670

    Abstract

    Synapsin I, the major phosphoprotein of synaptic vesicles, is thought to play a central role in neurotransmitter release. Here we introduce a null mutation into the murine synapsin I gene by homologous recombination. Mice with no detectable synapsin I manifest no apparent changes in well-being or gross nervous system function. Thus, synapsin I is not essential for neurotransmitter release. Electrophysiology reveals that mice lacking synapsin I exhibit a selective increase in paired pulse facilitation, with no major alterations in other synaptic parameters such as long-term potentiation. In addition to potential redundant functions shared with other proteins, synapsin I in normal mice may function to limit increases in neurotransmitter release elicited by residual Ca2+ after an initial stimulus.

    View details for Web of Science ID A1993MH74900012

    View details for PubMedID 7902212

  • EXAMINATION OF TEA-INDUCED SYNAPTIC ENHANCEMENT IN AREA CA1 OF THE HIPPOCAMPUS - THE ROLE OF VOLTAGE-DEPENDENT CA-2+ CHANNELS IN THE INDUCTION OF LTP JOURNAL OF NEUROSCIENCE Huang, Y. Y., Malenka, R. C. 1993; 13 (2): 568-576

    Abstract

    The role of voltage-dependent Ca2+ channels (VDCCs) in the induction of long-term potentiation (LTP) in the CA1 region of rat hippocampus was determined by examining the relationship between LTP and the long-lasting synaptic enhancement induced by extracellular application of tetraethylammonium (TEA). Consistent with previous findings (Aniksztejn and Ben-Ari, 1991), the TEA-induced synaptic enhancement did not require NMDA receptor activation. It was blocked by the L-type VDCC antagonist nifedipine or by intracellular injection of the Ca2+ chelator 1,2-bis(2-amino-phenoxy)ethane N,N,N',N'-tetra-acetic acid (BAPTA) and could be mimicked by direct activation of VDCCs with repetitive depolarizing current pulses. In contrast to its effect on TEA-induced synaptic enhancement, nifedipine had no effect on the magnitude or duration of NMDA receptor-dependent LTP. Saturation of NMDA receptor-dependent LTP reduced the magnitude of the TEA-induced synaptic enhancement. Similarly, increasing synaptic strength by initial application of TEA reduced the magnitude of the subsequent tetanus-induced LTP. Like LTP, the TEA-induced synaptic enhancement did not significantly affect paired-pulse facilitation. These results suggest that dihydropyridine-sensitive VDCCs do not normally contribute to the induction of NMDA receptor-dependent LTP even though their repetitive activation can generate an increase in synaptic strength. The mutual occlusion of LTP and TEA-induced synaptic enhancement suggests that they share a common expression mechanism and perhaps are generated by activation of common Ca(2+)-dependent intracellular processes.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993KL12300013

    View details for PubMedID 8381168

  • THE INFLUENCE OF PRIOR SYNAPTIC ACTIVITY ON THE INDUCTION OF LONG-TERM POTENTIATION SCIENCE Huang, Y. Y., Colino, A., Selig, D. K., Malenka, R. C. 1992; 255 (5045): 730-733

    Abstract

    Long-term potentiation (LTP) is an extensively studied model of synaptic plasticity, in part because it is a plausible biological correlate for the Hebbian synaptic modification that forms the basis for theoretical models of neural development, learning, and memory. Although these models must incorporate algorithms that constrain synaptic weight changes, physiological evidence for such mechanisms is limited. Examination of LTP in area CA1 of the hippocampus revealed that the threshold for LTP induction was not fixed but could be strongly influenced by the recent history of synaptic activity. This effect was transient, synapse-specific, and dependent on postsynaptic N-methyl-D-aspartate (NMDA) receptor activation. These results suggest that the threshold for LTP induction may be continually adjusted according to the recent history of NMDA receptor activation and provide a physiological mechanism by which LTP can be transiently inhibited.

    View details for Web of Science ID A1992HC50600043

    View details for PubMedID 1346729

  • CHARACTERIZATION OF THE INTEGRATION TIME FOR THE STABILIZATION OF LONG-TERM POTENTIATION IN AREA-CA1 OF THE HIPPOCAMPUS JOURNAL OF NEUROSCIENCE Colino, A., Huang, Y. Y., Malenka, R. C. 1992; 12 (1): 180-187

    Abstract

    In area CA1 of the hippocampus, synaptic activation of NMDA receptors during postsynaptic depolarization can generate either a decremental synaptic potentiation termed short-term potentiation (STP) or stable, long-term potentiation (LTP). Examining the relationship between these two forms of synaptic enhancement should provide information about the intracellular processes responsible for the stabilization of LTP. Using the hippocampal slice preparation, initial experiments confirmed that STP can be generated either by a weak tetanus or by pairing a single EPSP with postsynaptic depolarization. Following the generation of submaximal LTP, application of a weak, STP-inducing tetanus resulted in STP (not LTP), suggesting that the processes responsible for stabilizing LTP must be activated during induction and cannot be accessed at later times. To determine the interval over which processes activated during STP can be integrated and result in stable LTP (the "integration time" for the stabilization of LTP), a fixed number of afferent stimuli were given at varying intervals (5-60 sec) during postsynaptic depolarization. Using either extracellular or whole-cell recording, LTP was rarely (11% of experiments) elicited at 1 min intervals and frequently (76% of experiments) elicited at 10 sec intervals. These results indicate that following a single EPSP during postsynaptic depolarization, the processes responsible for the stabilization of LTP decay significantly within approximately 1 min, although this value may depend on the level of activation of the requisite intracellular processes.

    View details for Web of Science ID A1992HA64400016

    View details for PubMedID 1530869

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