Bio

Academic Appointments


Administrative Appointments


  • Director of Graduate Studies, Dept. Molecular and Cellular Physiology (2003 - 2012)
  • Committee on Graduate Admissions & Program (CGAP), School of Medicine (2000 - 2012)
  • Chair, Admissions Committee, Dept. Molecular and Cellular Physiology (2005 - 2012)
  • Senator at large, Medical School Faculty Senate (2004 - 2009)
  • Director of Admissions, Neurosciences Graduate Program (1997 - 2003)
  • Executive Committee, Neurosciences Graduate Program (1995 - 2003)
  • MSTP Admissions Committee, MSTP (1995 - 1999)
  • Director of Graduate Studies, Dept. Molecular and Cellular Physiology (1990 - 1997)
  • Graduate Admission Committee, Dept. Molecular and Cellular Physiology (1990 - 1997)
  • Committee of Five, School of Medicine (1994 - 1995)
  • Departmental Senator, Medical School Faculty Senate (1990 - 1995)

Honors & Awards


  • Young Investigator Award, Society for Neuroscience (.)
  • Lucille P. Markey Scholar, Lucile P. Markey Charitable Trust (.)

Professional Education


  • Ph.D., Univ.of Calif. San Francisco, Neurosciences (1984)
  • B.S., University of California, Irvine, Biological Sciences (1979)

Community and International Work


  • MBL Neurobiology Course, Woods Hole, MA

    Topic

    Neurobiology

    Partnering Organization(s)

    Marine Biological Laboratory, Woods Hole, MA

    Populations Served

    Graduate Students and Postdoctoral Fellows

    Location

    US

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Our laboratory is interested in the basic function, plasticity and modulation of Central Nervous System synapses, and their pathophysiology in Azheimer’s Disease as related to the functions of endocannabinoids. We use primarily electrophysiogical techniques along with high-resolution imaging to dissect the function of synapses undergoing changes due either to external stimuli, disease states or internal modulation, with an eye to understanding how those changes may affect behavior and memory.

Recent projects in the laboratory include a study of the role of the amyloid peptide A-beta in modulating synaptic inhibition through an action on the endogenous cannabinoid system of the hippocampus; the role of the Fragile X mental retardation protein in the formation of neural circuits, an array tomographic study on the influence of synaptic plasticity on the number of synapses made in neural microcircuits, and the characterization of synaptic plasticity states.

Studies in the lab are carried out using a full range of electrophysiological techniques including extracellular field potential recording, intracellular recording,whjole cell and single channel recording in hippocampal slices and cultured neurons. In addition we utilize high resolution imaging of synaptically connected pairs of neurons using array tomography and CLARITY techniques.

Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Glutamate receptor subunit GluA1 is necessary for long-term potentiation and synapse unsilencing, but not long-term depression in mouse hippocampus BRAIN RESEARCH Selcher, J. C., Xu, W., Hanson, J. E., Malenka, R. C., Madison, D. V. 2012; 1435: 8-14

    Abstract

    Receptor subunit composition is believed to play a major role in the synaptic trafficking of AMPA receptors (AMPARs), and thus in activity-dependent synaptic plasticity. To isolate a physiological role of GluA1-containing AMPARs in area CA3 of the hippocampus, pair recordings were performed in organotypic hippocampal slices taken from genetically modified mice lacking the GluA1 subunit. We report here that long-term potentiation (LTP) is impaired not only at active but also at silent synapses when the GluA1 subunit is absent. The GluA1 knockout mice also exhibited reduced AMPAR-mediated evoked currents between pairs of CA3 pyramidal neurons under baseline conditions suggesting a significant role for GluA1-containing AMPARs in regulating basal synaptic transmission. In two independent measures, however, long-term depression (LTD) was unaffected in tissue from these mice. These data provide a further demonstration of the fundamental role that GluA1-containing AMPARs play in activity-dependent increases in synaptic strength but do not support a GluA1-dependent mechanism for reductions in synaptic strength.

    View details for DOI 10.1016/j.brainres.2011.11.029

    View details for Web of Science ID 000301318400002

    View details for PubMedID 22197030

  • Altered Hippocampal Synaptic Physiology in Aged Parkin-Deficient Mice NEUROMOLECULAR MEDICINE Hanson, J. E., Orr, A. L., Madison, D. V. 2010; 12 (3): 270-276

    Abstract

    We examined synaptic function in the hippocampus of aged mice deficient for the Parkinson's disease-linked protein, parkin. Surprisingly, heterozygous but not homozygous parkin-deficient mice exhibited impairments in basal excitatory synaptic strength. Similarly heterozygous mice exhibited broad deficits in paired-pulse facilitation, while homozygous parkin-deficient mice exhibited more restricted deficits. In contrast to the measurements of basal synaptic function, synaptic plasticity was not altered in aged heterozygous parkin-deficient mice, but was enhanced in aged homozygous parkin-deficient mice, due to an absence of age-related decline. These findings of differential synaptic phenotypes in heterozygous vs. homozygous parkin deficiency suggest compensatory responses to genetic abnormalities could play an important role during the development of pathology in response to parkin deficiency.

    View details for DOI 10.1007/s12017-010-8113-y

    View details for Web of Science ID 000281259200009

    View details for PubMedID 20232175

  • AMPA receptor subunits define properties of state-dependent synaptic plasticity JOURNAL OF PHYSIOLOGY-LONDON Emond, M. R., Montgomery, J. M., Huggins, M. L., Hanson, J. E., Mao, L., Huganir, R. L., Madison, D. V. 2010; 588 (11): 1929-1946

    Abstract

    Many synapses undergo immediate and persistent activity-dependent changes in strength via processes that fall under the umbrella of synaptic plasticity. It is known that this type of synaptic plasticity exhibits an underlying state dependence; that is, as synapses change in strength they move into distinct 'states' that are defined by the mechanism and ability to undergo future plasticity. In this study, we have investigated the molecular mechanisms that underlie state-dependent synaptic plasticity. Using intracellular application of peptides that mimic the C-terminal tail sequences of GluR1 and GluR2 AMPA receptor subtypes, combined with paired recordings of minimal synaptic connections, we have shown that AMPA receptor subtypes present in the membrane at a given time confer some properties of plasticity states. These data show that during synaptic plasticity, AMPA receptor subtypes are differentially stabilized by postsynaptic density proteins in or out of the postsynaptic membrane, and this differential synaptic expression of different AMPA receptor subtypes defines distinct synaptic states.

    View details for DOI 10.1113/jphysiol.2010.187229

    View details for Web of Science ID 000278195900021

    View details for PubMedID 20351044

  • Presynaptic Fmr1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome JOURNAL OF NEUROSCIENCE Hanson, J. E., Madison, D. V. 2007; 27 (15): 4014-4018

    Abstract

    Almost all female and some male fragile X syndrome (FXS) patients are mosaic for expression of the FMR1 gene, yet all research in models of FXS has been in animals uniformly lacking Fmr1 expression. Therefore, we developed a system allowing neuronal genotype to be visualized in vitro in mouse brain slices mosaic for Fmr1 expression. Whole-cell recordings from individual pairs of presynaptic and postsynaptic neurons in organotypic hippocampal slices were used to probe the cell-autonomous effects of Fmr1 genotype in mosaic networks. These recordings revealed that wild-type presynaptic neurons formed synaptic connections at a greater rate than presynaptic neurons lacking normal Fmr1 function in mosaic networks. At the same time, the postsynaptic Fmr1 genotype did not influence the probability that a neuron received synaptic connections. Asymmetric presynaptic function during development of the brain could result in a decreased participation in network function by the portion of neurons lacking FMR1 expression.

    View details for DOI 10.1523/JNEUROSCI.4717-06.2007

    View details for Web of Science ID 000245810100013

    View details for PubMedID 17428978

  • The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome JOURNAL OF PHYSIOLOGY-LONDON Hanson, J. E., Blank, M., Valenzuela, R. A., Garner, C. C., Madison, D. V. 2007; 579 (1): 53-67

    Abstract

    Down's syndrome (DS) is the most common cause of mental retardation, and memory impairments are more severe in DS than in most if not all other causes of mental retardation. The Ts65Dn mouse, a genetic model of DS, exhibits phenotypes of DS, including memory impairments indicative of hippocampal dysfunction. We examined functional synaptic connectivity in area CA3 of the hippocampus of Ts65Dn mice using organotypic slice cultures as a model. We found reductions in multiple measures of synaptic function in both excitatory and inhibitory inputs to pyramidal neurons in CA3 of the Ts65Dn hippocampus. However, associational synaptic connections between pyramidal neurons were more abundant and more likely to be active rather than silent in the Ts65Dn hippocampus. Synaptic potentiation was normal in these associational connections. Decreased overall functional synaptic input onto pyramidal neurons expressed along with the specific hyperconnectivity of associational connections between pyramidal neurons will result in predictable alterations of CA3 network function, which may contribute to the memory impairments seen in DS.

    View details for DOI 10.1113/jphysiol.2006.114868

    View details for Web of Science ID 000244099400004

    View details for PubMedID 17158177

  • Toward a unified hypothesis of interneuronal modulation JOURNAL OF PHYSIOLOGY-LONDON Madison, D. V., McQuiston, A. R. 2006; 570 (3): 435-435

    View details for DOI 10.1113/jphysiol.2005.103937

    View details for Web of Science ID 000234673000003

    View details for PubMedID 16373382

  • Blocking polysynaptic inhibition via opioid receptor activation isolates excitatory synaptic currents without triggering epileptiform activity in organotypic hippocampal slices JOURNAL OF NEUROSCIENCE METHODS Hanson, J. E., Emond, M. R., Madison, D. V. 2006; 150 (1): 8-15

    Abstract

    The abundance of synaptic connectivity in the cultured hippocampal slice preparation allows measurements of the unitary excitatory connection between pairs of pyramidal neurons using simultaneous presynaptic and postsynaptic intracellular recordings. However, the useful yield of these recordings can be greatly reduced by the presence of polysynaptic inhibition that occludes the measurement of the monosynaptic excitatory postsynaptic current (EPSC). We have found that the traditional method of eliminating contaminating synaptic inhibition with GABA receptor antagonists is of limited usefulness because the recurrent excitatory connections in organotypic slices cause epileptiform bursting in the absence of inhibitory function. This bursting obscures EPSCs to an even greater extent than the normally occurring polysynaptic inhibitory transmission. Here, we report a new method for isolating monosynaptic EPSCs using the mu-opioid agonist peptide DAMGO to reduce polysynaptic inhibition during these recordings. Activation of mu-opioid receptors is known to hyperpolarize inhibitory neurons. We found that DAMGO application reduces the amplitude and frequency of polysynaptic inhibition, allowing isolation of the excitatory connection between the two neurons being recorded. Furthermore, because inhibitory function is not completely eliminated by DAMGO application, epileptiform bursting very rarely develops. Therefore, the use of DAMGO to prevent polysynaptic inhibition without causing epileptiform bursting provides a useful tool to substantially increase the yield of experiments measuring the unitary excitatory connection between pyramidal neurons in the cultured hippocampal slice preparation.

    View details for DOI 10.1016/j.jneumeth.2005.04.022

    View details for Web of Science ID 000234773200002

    View details for PubMedID 16081163

  • Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state BMC NEUROSCIENCE Montgomery, J. M., Selcher, J. C., Hanson, J. E., Madison, D. V. 2005; 6

    Abstract

    The N-methyl-D-aspartate (NMDA)-type glutamate receptor expressed at excitatory glutamatergic synapses is required for learning and memory and is critical for normal brain function. At a cellular level, this receptor plays a pivotal role in triggering and controlling synaptic plasticity. While it has been long recognized that this receptor plays a regulatory role, it was considered by many to be itself immune to synaptic activity-induced plasticity. More recently, we and others have shown that NMDA receptor-mediated synaptic responses can be subject to activity-dependent depression.Here we show that depression of synaptic transmission mediated by NMDA receptors displays a state-dependence in its plasticity; NMDA receptors are resistant to activity-induced changes at silent and recently-silent synapses. Once synapses transition to the active state however, NMDA receptors become fully 'plastic'. This state-dependence is identical to that shown by the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. Furthermore, the down-regulation of NMDAR-mediated responses during synaptic depression is prevented by disruption of dynamin-dependent endocytosis.NMDA receptor-mediated synaptic responses are plastic in a state-dependent manner. Depending on the plasticity state in which a synapse currently resides, NMDA receptors will either be available or unavailable for down-regulation. The mechanism underlying the down-regulation of NMDA receptor-mediated synaptic responses is endocytosis of the NMDA receptor. Other potential mechanisms, such as receptor diffusion along the plane of the membrane, or changes in the activity of the channel are not supported. The mechanisms of AMPA receptor and NMDA receptor endocytosis appear to be tightly coupled, as both are either available or unavailable for endocytosis in the same synaptic states. Endocytosis of NMDA receptors would serve as a potent mechanism for metaplasticity. Such state-dependent regulation of NMDAR endocytosis will provide fundamental control over downstream NMDA receptor-dependent plasticity of neuronal circuitry.

    View details for DOI 10.1186/1471-2202-6-48

    View details for Web of Science ID 000231267500001

    View details for PubMedID 16042781

  • Discrete synaptic states define a major mechanism of synapse plasticity TRENDS IN NEUROSCIENCES Montgomery, J. M., Madison, D. V. 2004; 27 (12): 744-750

    Abstract

    Synapses can change their strength in response to afferent activity, a property that might underlie a variety of neural processes such as learning, network synaptic weighting, synapse formation and pruning. Recent work has shown that synapses change their strength by jumping between discrete mechanistic states, rather than by simply moving up and down in a continuum of efficacy. Coincident with this, studies have provided a framework for understanding the potential mechanistic underpinnings of synaptic plastic states. Synaptic plasticity states not only represent a new and fundamental property of CNS synapses, but also can provide a context for understanding outstanding issues in synaptic function, plasticity and development.

    View details for Web of Science ID 000225540000009

    View details for PubMedID 15541515

  • SNAP-25 Ser187 does not mediate phorbol ester enhancement of hippocampal synaptic transmission NEUROPHARMACOLOGY Finley, M. F., Scheller, R. H., Madison, D. V. 2003; 45 (6): 857-862

    Abstract

    Phorbol esters, activators of protein kinase C (PKC), have been shown to enhance synaptic transmission. One potential downstream target of PKC in the presynaptic terminal is the soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) SNAP-25, which has a PKC phosphorylation site in its C-terminal coil centered at serine 187 (S187/Ser187). We examined the role of S187 in hippocampal synaptic transmission. After proteolytic cleavage of native SNAP-25 by botulinum neurotoxin E (BoNT/E), synaptic transmission was restored in a subset of transfected CA3 pyramidal cells with a toxin-resistant form of SNAP-25 containing unaltered S187 (Swt), S187 mutated to alanine (SA) or S187 mutated to glutamate (SE). We observed that phorbol-12,13-diacetate (PDAc, 10 microM) induced potentiation of neurotransmission to a similar degree for both Swt and SA (2.4-fold and 3.1-fold increase, respectively). Furthermore, basal levels of transmission mediated by SE were reduced relative to that of Swt (failure rates of 72% and 41%, respectively). Together, these data suggest that phosphorylation of SNAP-25 S187 does not mediate the observed enhancement of neurotransmission by phorbol esters at hippocampal synapses.

    View details for DOI 10.1016/S0028-3908(03)00238-1

    View details for Web of Science ID 000186297500015

    View details for PubMedID 14529723

  • State-dependent heterogeneity in synaptic depression between pyramidal cell pairs NEURON Montgomery, J. M., Madison, D. V. 2002; 33 (5): 765-777

    Abstract

    Paired recordings between CA3 pyramidal neurons were used to study the properties of synaptic plasticity in active and silent synapses. Synaptic depression is accompanied by decreases in both AMPAR and NMDAR function. The mechanisms of synaptic depression, and the potential to undergo activity-dependent plastic changes in efficacy, differ depending on whether a synapse is active, recently silent, or potentiated. These results suggest that silent and active synapses represent distinct synaptic "states," and that once unsilenced, synapses express plasticity in a graded manner. The state in which a synapse resides, and the states recently visited, determine its potential and mechanism for undergoing subsequent plastic changes.

    View details for Web of Science ID 000174286200012

    View details for PubMedID 11879653

  • The core membrane fusion complex governs the probability of synaptic vesicle fusion but not transmitter release kinetics JOURNAL OF NEUROSCIENCE Finley, M. F., Patel, S. M., Madison, D. V., Scheller, R. H. 2002; 22 (4): 1266-1272

    Abstract

    Synaptic vesicle fusion is driven by the formation of a four-helical bundle composed of soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptors (SNAREs). Exactly how the structural interactions that lead to the formation of this complex relate to neurotransmitter release is not well understood. To address this question, we used a strategy to "rescue" synaptic transmission after proteolytic cleavage of the synaptosome-associated protein of 25 kDa (SNAP-25) by botulinum neurotoxin E (BoNtE). Transfection of CA3 hippocampal pyramidal cells with BoNtE-resistant SNAP-25 restored synaptic transmission. Additional mutations that alter the interaction between SNAP-25 C-terminal coil and the other SNARE coils dramatically reduce transmitter release probability but leave the kinetics of synaptic responses unaltered. These data indicate that at synapses, SNARE interactions are necessary for fusion but are not the rate-limiting step of neurotransmission.

    View details for Web of Science ID 000174062300011

    View details for PubMedID 11850454

  • Preparation of hippocampal brain slices. Current protocols in neuroscience / editorial board, Jacqueline N. Crawley ... [et al.] Madison, D. V., Edson, E. B. 2001; Chapter 6: Unit 6 4-?

    Abstract

    This unit presents a procedure for the preparation of acute mammalian hippocampal slices for electrophysiological recording. Although this protocol should not be taken as the only means of making brain slices, it is a widely-used typical procedure. It is simple and straightforward. It can be used on a variety of mammalian species, though it is discussed here for use in rats.

    View details for DOI 10.1002/0471142301.ns0604s00

    View details for PubMedID 18428514

  • The grass roots of synapse suppression NEURON Montgomery, J. M., Madison, D. V. 2001; 29 (3): 567-570

    View details for Web of Science ID 000167868900007

    View details for PubMedID 11301017

  • Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation NEURON Montgomery, J. M., Pavlidis, P., Madison, D. V. 2001; 29 (3): 691-701

    Abstract

    The activation of silent synapses is a proposed mechanism to account for rapid increases in synaptic efficacy such as long-term potentiation (LTP). Using simultaneous recordings from individual pre- and postsynaptic neurons in organotypic hippocampal slices, we show that two CA3 neurons can be connected entirely by silent synapses. Increasing release probability or application of cyclothiazide does not produce responses from these silent synapses. Direct measurement of NMDAR-mediated postsynaptic responses in all-silent synaptic connections before and after LTP induction show no change in failure rate, amplitude, or area. These data do not support hypotheses that synapse silent results from presynaptic factors or that LTP results from increases in presynaptic glutamate release. LTP is also associated with an increase in postsynaptic responsiveness to exogenous AMPA. We conclude that synapse silence, activation, and expression of LTP are postsynaptic.

    View details for Web of Science ID 000167868900018

    View details for PubMedID 11301028

  • A novel SNAP25-caveolin complex correlates with the onset of persistent synaptic potentiation JOURNAL OF NEUROSCIENCE Braun, J. E., Madison, D. V. 2000; 20 (16): 5997-6006

    Abstract

    We have identified synaptic protein complexes in intact rat hippocampal slices using the rapid chemical cross-linking reagent paraformaldehyde. Cellular proteins were rapidly cross-linked, solubilized, separated electrophoretically by SDS-PAGE, and then identified immunologically. Multiple complexes containing syntaxin, the synaptosomal-associated protein of 25 kDa (SNAP25), and vesicle-associated membrane protein (VAMP) were observed to coexist in a single hippocampal slice including a 100 kDa cross-linked protein complex that exhibited the same electrophoretic migration as a member of the previously identified SDS-resistant soluble N-ethylmaleimide-sensitive fusion attachment protein receptor "core" of the 20 S complex. A VAMP-synaptophysin complex, reported previously in vitro, was also observed in the hippocampal slices. This study links biochemical and physiological studies involving presynaptic proteins implicated in secretion and confirms that these proteins that have been studied extensively previously in the presence of detergent do form "bona fide" cellular complexes. Importantly, we have also detected additional novel protein complexes that do not correspond to complexes identified previously in vitro. After the induction of persistent synaptic potentiation, an abundant 40 kDa SNAP25-caveolin1 complex was observed. The SNAP25-caveolin1 complex was not abundant in control slices and, therefore, represents the first demonstration of a reorganization of protein complexes in intact hippocampal slices during the induction of synaptic potentiation. The interaction between caveolin1 and SNAP25 was confirmed biochemically by demonstration of the association of caveolin with recombinant-immobilized SNAP25 and by the coimmunoprecipitation of SNAP25 using caveolin-specific antisera. Caveolin1, like SNAP25, was observed to be abundant in isolated hippocampal nerve terminals (synaptosomes). Immunofluorescent studies demonstrated that both SNAP25 and caveolin1 are present in neurons and colocalize in axonal varicosities. These results suggest that a short-lasting SNAP25-caveolin interaction may be involved in the early phase of synaptic potentiation.

    View details for Web of Science ID 000088676400015

    View details for PubMedID 10934248

  • Presynaptic protein kinase activity supports long-term potentiation at synapses between individual hippocampal neurons JOURNAL OF NEUROSCIENCE Pavlidis, P., Montgomery, J., Madison, D. V. 2000; 20 (12): 4497-4505

    Abstract

    Simultaneous microelectrode recording from two individual synaptically connected neurons enables the direct analysis of synaptic transmission and plasticity at a minimal synaptic connection. We have recorded from pairs of CA3 pyramidal neurons in organotypic hippocampal slices to examine the properties of long-term potentiation (LTP) at such minimal connections. LTP in minimal connections was found to be identical to the NMDA-dependent LTP expressed by CA3-CA1 synapses, demonstrating this system provides a good model for the study of the mechanisms of LTP expression. The LTP at minimal synaptic connections does not behave as a simple increase in transmitter release probability, because the amplitude of unitary EPSCs can increase several-fold, unlike what is observed when release probability is increased by raising extracellular calcium. Taking advantage of the relatively short axon connecting neighboring CA3 neurons, we found it feasible to introduce pharmacological agents to the interior of presynaptic terminals by injection into the presynaptic soma and have used this technique to investigate presynaptic effects on basal transmission and LTP. Presynaptic injection of nicotinamide reduced basal transmission, but LTP in these pairs was essentially normal. In contrast, presynaptic injection of H-7 significantly depressed LTP but not basal transmission, indicating a specific role of presynaptic protein kinases in LTP. These results demonstrate that pharmacological agents can be directly introduced into the presynaptic cell and that a purely presynaptic perturbation can alter this plasticity.

    View details for Web of Science ID 000087448500017

    View details for PubMedID 10844019

  • Muscarinic receptor activity has multiple effects on the resting membrane potentials of CA1 hippocampal interneurons JOURNAL OF NEUROSCIENCE McQuiston, A. R., Madison, D. V. 1999; 19 (14): 5693-5702

    Abstract

    Inhibitory interneurons appear to be an important target for the muscarinic actions of cholinergic inputs to the hippocampus. We investigated the effect of muscarinic receptor activity on the membrane potential (V(m)) and currents of rat hippocampal CA1 interneurons using whole-cell recording from visually identified CA1 interneurons. The predominant response observed was a muscarinic depolarization that was detected in interneurons from all layers of CA1. This depolarization was mediated by at least two mechanisms: a reduction in a potassium current and a mechanism that depended on extracellular sodium. Other interneurons responded to muscarinic agonists with a hyperpolarization or a biphasic response (hyperpolarization followed by depolarization). Hyperpolarizations and biphasic responses were found in all layers of CA1 but more frequently in stratum radiatum and stratum lacunosum moleculare. Muscarinic hyperpolarization was caused by the activation of a barium- and cesium-sensitive inwardly rectifying potassium channel. A small number of interneurons, primarily in or bordering the stratum pyramidale, produced slow membrane potential (0.04 Hz) oscillations. Many interneurons did not respond to muscarinic activity at all; half of these were in the stratum oriens. There was no strong correlation between any changes in V(m) response to muscarine and morphology, as determined by reconstruction of the interneurons. It was not possible to predict the morphology or the layer distribution of an interneuron based on the type of muscarinic membrane potential response it had. This lack of correlation between muscarinic function and morphology implies a greater complexity of interneuron function than has been realized previously.

    View details for Web of Science ID 000081377600001

    View details for PubMedID 10407010

  • Muscarinic receptor activity induces an afterdepolarization in a subpopulation of hippocampal CA1 interneurons JOURNAL OF NEUROSCIENCE McQuiston, A. R., Madison, D. V. 1999; 19 (14): 5703-5710

    Abstract

    Cholinergic input to the hippocampus may be involved in important behavioral functions and the pathophysiology of neurodegenerative diseases. Muscarinic receptor activity in interneurons of the hippocampus may play a role in these actions. In this study, we investigated the effects of muscarinic receptor activity on the excitability of different subtypes of interneurons in rat hippocampal CA1. Most interneurons displayed an afterhyperpolarizing potential (AHP) after depolarization by injected current or synaptic stimulation. In the presence of a muscarinic agonist, the AHP of a subset of these interneurons was replaced by an afterdepolarization (ADP), often of sufficient magnitude to evoke action potentials in the absence of further stimulation. The ADP was insensitive to cadmium and low extracellular calcium. It was blocked by low extracellular sodium but not by tetrodotoxin or low concentrations of amiloride. Muscarinic ADPs were sometimes observed in isolation but were often accompanied by depolarizing, hyperpolarizing, or biphasic changes in the membrane potential. Interneurons with muscarinic ADPs were found in all strata of CA1 and did not fall into a single morphological classification. The potential functions of the prolonged action potential output of interneurons produced by the ADP could include changes in hippocampal circuit properties and facilitation of the release of peptide cotransmitters in these interneurons.

    View details for Web of Science ID 000081377600002

    View details for PubMedID 10407011

  • Synaptic transmission in pair recordings from CA3 pyramidal cells in organotypic culture JOURNAL OF NEUROPHYSIOLOGY Pavlidis, P., Madison, D. V. 1999; 81 (6): 2787-2797

    Abstract

    We performed simultaneous whole cell recordings from pairs of monosynaptically coupled hippocampal CA3 pyramidal neurons in organotypic slices. Stimulation of an action potential in a presynaptic cell resulted in an AMPA-receptor-mediated excitatory postsynaptic current (EPSC) in the postsynaptic cell that averaged approximately 34 pA. The average size of EPSCs varied in amplitude over a 20-fold range across different pairs. Both paired-pulse facilitation and depression were observed in the synaptic current in response to two presynaptic action potentials delivered 50 ms apart, but the average usually was dominated by depression. In addition, the amplitude of the second EPSC depended on the amplitude of the first EPSC, indicating competition between successive events for a common resource that is not restored within the 50-ms interpulse interval. Variation in the synaptic strength among pairs could arise from a variety of sources. Our data from anatomic reconstruction, 1/CV2 analysis, paired-pulse analysis, and manipulations of calcium/magnesium ratio suggest that differences in quantal size and release probability do not appear to vary sufficiently to fully account for the observed differences in amplitude. Thus it seems most likely that the variability in EPSC amplitude between pairs arises primarily from differences in the number of functional synapses. Injections of the calcium chelator bis-(o-aminophenoxy)-N, N,N',N'-tetraacetic acid into the presynaptic neuron resulted in a rapid and nearly complete block of transmission, whereas injection of the slower-acting chelator EGTA resulted in a variable and partial block. In addition to demonstrating the feasibility of manipulating the intracellular presynaptic environment by injection into the presynaptic soma, these data, and the EGTA results in particular may suggest variability in the linkage between calcium entry sites an release sites in these synapses.

    View details for Web of Science ID 000081005800018

    View details for PubMedID 10368397

  • Impaired synaptic plasticity in mice carrying the Huntington's disease mutation HUMAN MOLECULAR GENETICS Usdin, M. T., Shelbourne, P. F., Myers, R. M., Madison, D. V. 1999; 8 (5): 839-846

    Abstract

    Cognitive impairment is an early symptom of Huntington's disease (HD). Mice engineered to carry the HD mutation in the endogenous huntingtin gene showed a significant reduction in long-term potentiation (LTP), a measure of synaptic plasticity often thought to be involved in memory. However, LTP could be induced in mutant slices by an 'enhanced' tetanic stimulus, implying that the LTP-producing mechanism is intact in mutant mice, but that their synapses are less able to reach the threshold for LTP induction. Mutant mice showed less post-tetanic potentiation than wild-type animals, and also showed decreased paired pulse facilitation, suggesting that excitatory synapses in HD mutant mice are impaired in their ability to sustain transmission during repetitive stimulation. We show that mutants, while normal in their ability to transmit at low frequencies, released significantly less glutamate during higher frequency synaptic activation. Thus, a reduced ability of Huntington synapses to respond to repetitive synaptic demand of even moderate frequency could result not only in a functional impairment of LTP induction, but could also serve as a substrate for the cognitive symptoms that comprise the early-stage pathology of HD.

    View details for Web of Science ID 000080109200013

    View details for PubMedID 10196373

  • Nicotinic receptor activation excites distinct subtypes of interneurons in the rat hippocampus JOURNAL OF NEUROSCIENCE McQuiston, A. R., Madison, D. V. 1999; 19 (8): 2887-2896

    Abstract

    We examined the function of nicotinic acetylcholine receptors (nAChRs) in interneurons of area CA1 of the rat hippocampus. CA1 interneurons could be classified into three categories based on nicotinic responses. The first class was depolarized by alpha7 nAChRs, found in all layers of CA1 and as a group, had axonal projections to all neuropil layers of CA1. The second class had both fast alpha7 and slow non-alpha7 nAChR depolarizing responses, was localized primarily to the stratum oriens, and had axonal projections to the stratum lacunosum-moleculare. The third group had no nicotinic response. This group was found in or near the stratum pyramidale and had axonal projections almost exclusively within and around this layer. Low concentrations (500 nM) of nicotine desensitized fast and slow nAChR responses. These findings demonstrate that there are distinct subsets of interneurons with regard to nicotinic receptor expression and with predictable morphological properties that suggest potential cellular actions for nicotinic receptor activation in normal CNS function and during nicotine abuse.

    View details for Web of Science ID 000079568300005

    View details for PubMedID 10191306

  • Excitatory actions of norepinephrine on multiple classes of hippocampal CA1 interneurons JOURNAL OF NEUROSCIENCE Bergles, D. E., Doze, V. A., Madison, D. V., Smith, S. J. 1996; 16 (2): 572-585

    Abstract

    Norepinephrine (NE) causes an increase in the frequency of inhibitory postsynaptic potentials in CA1 pyramidal neurons in vitro. The possibility that this increase in tonic inhibition is caused by an excitatory effect on inhibitory interneurons was investigated through whole-cell recordings from pyramidal cells and both whole-cell and cell-attached patch recordings from visualized interneurons in acute slices of rat hippocampus. Adrenergic agonists caused a large increase in the frequency and amplitude of spontaneous IPSCs recorded from pyramidal cells in the presence of ionotropic glutamate receptor blockers, but they had no effect on either the frequency or the amplitude of action potential-independent miniature IPSCs recorded in tetrodotoxin. This effect was mediated primarily by an alpha adrenoceptor, although a slight beta adrenoceptor-dependent increase in IPSCs was also observed. NE caused interneurons located in all strata to depolarize and begin firing action potentials. Many of these cells had axons that ramified throughout the stratum pyramidale, suggesting that they are responsible for the IPSCs observed in pyramidal neurons. This depolarization was also mediated by an alpha adrenoceptor and was blocked by a selective alpha 1- but not a selective alpha 2-adrenoceptor antagonist. However, a slight beta adrenoceptor-dependent depolarization was detected in those interneurons that displayed time-dependent inward rectification. In the presence of a beta antagonist, NE induced an inward current that reversed near the predicted K+ equilibrium potential and was not affected by changes in intracellular Cl- concentration. In the presence of an alpha 1 antagonist, NE induced an inwardly rectifying current at potentials negative to approximately -70 mV that did not reverse (between -130 and -60 mV), characteristics similar to the hyperpolarization-activated current (lh). However, the depolarizing action of NE is attributable primarily to the alpha 1 adrenoceptor-mediated decrease in K+ conductance and not the beta adrenoceptor-dependent increase in lh. These results provide evidence that NE increases action potential-dependent IPSCs in pyramidal neurons by depolarizing surrounding inhibitory interneurons. This potent excitatory action of NE on multiple classes of hippocampal interneurons may contribute to the NE-induced decrease in the spontaneous activity of pyramidal neurons and the antiepileptic effects of NE observed in vivo.

    View details for Web of Science ID A1996TP51900015

    View details for PubMedID 8551341

  • CALCIUM-CHANNEL INVOLVEMENT IN GABA(B) RECEPTOR-MEDIATED INHIBITION OF GABA RELEASE IN AREA CA1 OF THE RAT HIPPOCAMPUS JOURNAL OF NEUROPHYSIOLOGY Doze, V. A., Cohen, G. A., Madison, D. V. 1995; 74 (1): 43-53

    Abstract

    1. Experiments were performed in rat hippocampal slices to examine the nature of GABAergic inhibition of inhibitory synaptic transmission. In these experiments the effects of the gamma-aminobutyric acid-B (GABAB) receptor agonist, baclofen, and of subtype-selective calcium channel blockers were tested with the use of intracellular recordings of evoked inhibitory postsynaptic potentials (IPSPs) and whole cell recordings of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). 2. Baclofen inhibited evoked and spontaneous (action-potential-dependent) monosynaptic GABAA-mediated IPSPs and IPSCs but had no effect on the frequency of tetrodotoxin-resistant (action-potential-independent) miniature IPSCs recorded in CA1 pyramidal neurons. 3. Depolarizing GABAergic synaptic terminals by raising the extracellular potassium concentration caused an increase in action-potential-independent miniature IPSC frequency that could be inhibited by either baclofen or cadmium, a blocker of voltage-dependent calcium channels. In addition, under these depolarizing conditions, cadmium occluded the baclofen inhibition of miniature IPSCs. These data suggest that baclofen reduces only depolarization-induced, not quantal, GABA release and that it does so by decreasing presynaptic voltage-dependent calcium influx. 4. Experiments with subtype-selective calcium channel blockers demonstrate that the presynaptic action of baclofen was mediated through both omega-conotoxin-GVIA-sensitive and omega-agatoxin-IVA-sensitive, but not dihydropyridine-sensitive calcium channels.

    View details for Web of Science ID A1995RL65400005

    View details for PubMedID 7472344

  • REFLECTIONS ON CA2+-CHANNEL DIVERSITY, 1988-1994 TRENDS IN NEUROSCIENCES Tsien, R. W., Lipscombe, D., Madison, D., Bley, K., Fox, A. 1995; 18 (2): 52-54

    View details for Web of Science ID A1995QD40200005

    View details for PubMedID 7537405

  • Diffusible messengers and intercellular signaling: locally distributed synaptic potentiation in the hippocampus. Current topics in microbiology and immunology Madison, D. V., Schuman, E. M. 1995; 196: 5-6

    View details for PubMedID 7634824

  • AN ADP-RIBOSYLTRANSFERASE AS A POTENTIAL TARGET FOR NITRIC-OXIDE ACTION IN HIPPOCAMPAL LONG-TERM POTENTIATION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Schuman, E. M., Meffert, M. K., Schulman, H., Madison, D. V. 1994; 91 (25): 11958-11962

    Abstract

    Recent studies of long-term potentiation (LTP) in the CA1 region of the hippocampus have demonstrated that nitric oxide (NO) may be involved in some forms of LTP and have suggested that postsynaptically generated NO is a candidate to act as a retrograde messenger. However, the molecular target(s) of NO in LTP remain to be elucidated. The present study examined whether either of two potential NO targets, a soluble guanylyl cyclase or an ADP-ribosyltransferase (ADPRT; EC 2.4.2.31) plays a role in LTP. The application of membrane-permeant analogs of cGMP did not produce any long-lasting alterations in synaptic strength. In addition, application of a cGMP-dependent protein kinase inhibitor did not prevent LTP. We found that the CA1 tissue from hippocampus possesses an ADPRT activity that is dramatically stimulated by NO and attenuated by two different inhibitors of mono-ADPRT activity, phylloquinone and nicotinamide. The extracellular application of these same inhibitors prevented LTP. Postsynaptic injection of nicotinamide failed to attenuate LTP, suggesting that the critical site of ADPRT activity resides at a nonpostsynaptic locus. These results suggest that ADP-ribosylation plays a role in LTP and are consistent with the idea that an ADPRT may be a target of NO action.

    View details for Web of Science ID A1994PW70800040

    View details for PubMedID 7991564

  • INHIBITION OF HIPPOCAMPAL HEME OXYGENASE, NITRIC-OXIDE SYNTHASE, AND LONG-TERM POTENTIATION BY METALLOPORPHYRINS NEURON Meffert, M. K., Haley, J. E., Schuman, E. M., Schulman, H., Madison, D. V. 1994; 13 (5): 1225-1233

    Abstract

    Four potent metalloporphyrin inhibitors of heme oxygenase were used to assess whether carbon monoxide production was required for induction of LTP in the CA1 region of the hippocampus. Although the metalloporphyrins produced a similar and substantial inhibition of heme oxygenase activity in hippocampal slices, only two compounds reduced the amount of LTP elicited by tetanic stimulation (chromium mesoporphyrin IX and zinc protoporphyrin IX). Both chromium mesoporphyrin IX and zinc protoporphyrin IX inhibited nitric oxide synthase in the hippocampus; tin mesoporphyrin IX and zinc deuteroporphyrin IX bis glycol neither reduced LTP induction nor inhibited NOS activity, although they did inhibit heme oxygenase. None of these metalloporphyrins reversed established LTP. Thus, together these data do not support carbon monoxide as a mediator in either LTP induction or expression/maintenance and emphasize further the nonselectivity of some metalloporphyrins.

    View details for Web of Science ID A1994PU76300018

    View details for PubMedID 7524564

  • NITRIC-OXIDE AND SYNAPTIC FUNCTION ANNUAL REVIEW OF NEUROSCIENCE Schuman, E. M., Madison, D. V. 1994; 17: 153-183

    View details for Web of Science ID A1994NA54400005

    View details for PubMedID 7516125

  • COMMUNICATION OF SYNAPTIC POTENTIATION BETWEEN SYNAPSES OF THE HIPPOCAMPUS MOLECULAR AND CELLULAR MECHANISMS OF NEUROTRANSMITTER RELEASE Schuman, E. M., Madison, D. V. 1994; 29: 507-520

    View details for Web of Science ID A1994BB35S00029

    View details for PubMedID 7848729

  • PHORBOL ESTERS ENHANCE SYNAPTIC TRANSMISSION BY A PRESYNAPTIC, CALCIUM-DEPENDENT MECHANISM IN RAT HIPPOCAMPUS JOURNAL OF PHYSIOLOGY-LONDON Parfitt, K. D., Madison, D. V. 1993; 471: 245-268

    Abstract

    1. The effects of phorbol esters on evoked and spontaneous excitatory neurotransmission were studied in the CA1 area in the in vitro hippocampal slice preparation of the rat. Experiments were conducted using field potential recording and whole-cell voltage clamp of CA1 pyramidal neurons. 2. Pyramidal cells dialysed during whole-cell recording with EGTA-containing electrode solutions, unable to support the induction of long-term potentiation (LTP), still showed robust phorbol ester-induced potentiation of excitatory synaptic transmission. 3. Spontaneous miniature excitatory postsynaptic currents (EPSCs), recorded in whole-cell voltage clamp in the presence of tetrodotoxin and picrotoxin, had amplitudes ranging from 4 to 40 pA and occurred at an average frequency of 0.8-5 Hz. Neither the amplitude nor the frequency of spontaneous EPSCs was altered by cadmium, dihydropyridines, or omega-conotoxin GVIA. 4. The phorbol ester 4-beta-phorbol 12,13-diacetate increased the frequency of spontaneous miniature EPSCs without changing the shape of the EPSC amplitude distribution, suggesting that phorbol esters exert their potentiating effects presynaptically. 5. Blockade of voltage-dependent calcium channels with cadmium attenuated the phorbol-induced increase in spontaneous miniature EPSCs frequency. The phorbol ester-induced increase in miniature EPSC frequency was also attenuated by dihydropyridines, but not by omega-conotoxin GVIA. 6. Unlike spontaneous synaptic currents, stimulus-evoked synaptic currents were reduced by omega-conotoxin but not by nifedipine. 7. We conclude that the phorbol ester increases spontaneous release of glutamate by modulating an L-type channel that does not participate in stimulus-evoked neurotransmitter release.

    View details for Web of Science ID A1993MK55100014

    View details for PubMedID 8120806

  • PASS THE NITRIC-OXIDE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Madison, D. V. 1993; 90 (10): 4329-4331

    View details for Web of Science ID A1993LC72000001

    View details for PubMedID 7685098

  • ENHANCEMENT OF TRANSMISSION AT THE DEVELOPING RETINOGENICULATE SYNAPSE NEURON Mooney, R., Madison, D. V., Shatz, C. J. 1993; 10 (5): 815-825

    Abstract

    Axon terminals from retinal ganglion cells in the left and right eyes initially overlap with each other in the lateral geniculate nucleus of the neonatal ferret, then segregate into eye-specific layers via an activity-dependent process. Brain slices were used to show that, during this period of reorganization, retinal terminals within the lateral geniculate nucleus evoke excitatory postsynaptic currents composed of both NMDA and non-NMDA receptor-mediated currents. The amplitude of these currents could be enhanced for several tens of minutes to more than an hour by several bursts of high frequency synaptic stimulation, and the induction of enhancement appears to depend on NMDA receptor activation. Synaptic enhancement such as this could provide one of the physiological mechanisms by which retinal terminals segregate into eye-specific layers during development.

    View details for Web of Science ID A1993LD32200005

    View details for PubMedID 8388224

  • LONG-TERM POTENTIATION - KNOCKING OUT MEMORY DOOR NATURE Madison, D. V. 1992; 358 (6388): 626-627

    View details for Web of Science ID A1992JJ88200033

    View details for PubMedID 1323061

  • OPIOID INHIBITION OF GABA RELEASE FROM PRESYNAPTIC TERMINALS OF RAT HIPPOCAMPAL INTERNEURONS NEURON Cohen, G. A., Doze, V. A., Madison, D. V. 1992; 9 (2): 325-335

    Abstract

    Opiates and the opioid peptide enkephalin can cause indirect excitation of principal cortical neurons by reducing inhibitory synaptic transmission mediated by GABAergic interneurons. The mechanism by which opioids mediate these effects on interneurons is unknown, but enkephalin hyperpolarizes the somatic membrane potential of a variety of neurons in the brain, including hippocampal interneurons. We now report a new, more direct mechanism for the opioid-mediated reduction in synaptic inhibition. The enkephalin analog D-Ala2-Met5-enkephalinamide (DALA) decreases the frequency of miniature, action potential-independent, spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) without causing a change in their amplitude. Thus, we conclude that DALA inhibits the action potential-independent release of GABA through a direct action on interneuronal synaptic terminals. In contrast, DALA reduces the amplitude of action potential-evoked, GABA-mediated IPSCs, as well as decreases their frequency. This suggests that the opioid-mediated inhibition of non-action potential-dependent GABA release reveals a mechanism that contributes to reducing action potential-evoked GABA release, thereby decreasing synaptic inhibition.

    View details for Web of Science ID A1992JJ33200014

    View details for PubMedID 1497896

  • ISOPROTERENOL INCREASES THE PHOSPHORYLATION OF THE SYNAPSINS AND INCREASES SYNAPTIC TRANSMISSION IN DENTATE GYRUS, BUT NOT IN AREA CA1, OF THE HIPPOCAMPUS HIPPOCAMPUS Parfitt, K. D., Doze, V. A., Madison, D. V., Browning, M. D. 1992; 2 (1): 59-64

    Abstract

    Previous studies have shown that either norepinephrine (NE) or isoproterenol (ISO) enhances the slope of the field excitatory postsynaptic potential (EPSP) in the dentate gyrus of the rat hippocampal formation. In contrast, NE and ISO cause no increase in excitatory transmission in area CA1 of the hippocampus. The molecular mechanism underlying this brain region-specific increase in synaptic transmission is not known. The phosphorylation of synapsin I and synapsin II, two homologous presynaptic vesicle-associated proteins, is thought to promote neurotransmitter release. The authors have observed previously NE- and ISO-enhanced phosphorylation of synapsins I and II in the dentate gyrus. The purpose of this study was to determine whether ISO-stimulated phosphorylation also occurs in the CA1, where ISO has no effect on excitatory neurotransmission. These studies were correlated with electrophysiological studies in in vitro hippocampal slices. Superfusion of slices with ISO resulted in an increase in EPSP slope in the dentate but not in area CA1. The enhanced dentate EPSP returned to baseline levels within 30 minutes of washout of the drug. Isoproterenol produced corresponding increases in the phosphorylation of the synapsins in dentate slices but had no effect on these proteins in CA1 slices. Moreover, in dentate slices exposed to a 30-minute wash following incubation with ISO, phosphorylation of the synapsins returned to control levels. This close temporal and brain regional correlation between ISO stimulation of both synapsin phosphorylation and synaptic transmission suggests that the synapsin proteins may play a role in the synaptic potentiation produced by ISO in the dentate.

    View details for Web of Science ID A1992HD52200007

    View details for PubMedID 1339193

  • PROTEIN-KINASES AND LONG-TERM POTENTIATION ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Meffert, M. K., Parfitt, K. D., Doze, V. A., Cohen, G. A., Madison, D. V. 1991; 627: 2-9

    View details for Web of Science ID A1991GJ97100001

    View details for PubMedID 1679309

  • LTP, POST OR PRE - A LOOK AT THE EVIDENCE FOR THE LOCUS OF LONG-TERM POTENTIATION NEW BIOLOGIST Madison, D. V., Schuman, E. M. 1991; 3 (6): 549-557

    Abstract

    It seems self-evident that changes in the cellular synaptic function of the brain must underlie the formation and storage of cognitive memories. Because it has been identified as a brain area important in the formation of memory, the hippocampus has been a focus in the study of such synaptic changes. An activity-induced increase in hippocampal synaptic efficacy, known as long-term potentiation (LTP), has been widely studied as a potential substrate for memory. This paper briefly reviews some of the significant progress that has been made in understanding the cellular mechanisms that underlie LTP, including recent experiments dealing with its synaptic locus, or the question of whether the mechanism regulating LTP is pre- or postsynaptic.

    View details for Web of Science ID A1991GK72100004

    View details for PubMedID 1680385

  • SYNAPTIC LOCALIZATION OF ADRENERGIC DISINHIBITION IN THE RAT HIPPOCAMPUS NEURON Doze, V. A., Cohen, G. A., Madison, D. V. 1991; 6 (6): 889-900

    Abstract

    Norepinephrine is an endogenous neurotransmitter that reduces synaptic inhibition onto pyramidal neurons in the hippocampus by an action at an alpha-adrenergic receptor. The physiological mechanism of this disinhibition was previously not known, except that it occurred at a site presynaptic to the inhibited pyramidal cell. In this paper we present evidence that adrenergic disinhibition is restricted to the early phase of the evoked inhibitory postsynaptic potential in area CA1 of the hippocampus. The locus of disinhibition does not appear to reside in the interneuronal terminal, axon, or cell body. Instead, adrenergic agonists appear to reduce evoked synaptic inhibition by depressing excitatory synapses that activate the interneuron.

    View details for Web of Science ID A1991FT94900004

    View details for PubMedID 1675862

  • MECHANISMS UNDERLYING LONG-TERM POTENTIATION OF SYNAPTIC TRANSMISSION ANNUAL REVIEW OF NEUROSCIENCE Madison, D. V., Malenka, R. C., Nicoll, R. A. 1991; 14: 379-397

    View details for Web of Science ID A1991EZ46700016

    View details for PubMedID 1851607

  • PERSISTENT PROTEIN-KINASE ACTIVITY UNDERLYING LONG-TERM POTENTIATION NATURE Malinow, R., Madison, D. V., Tsien, R. W. 1988; 335 (6193): 820-824

    Abstract

    Long-term potentiation (LTP) of synaptic transmission in the hippocampus is a much-studied example of synaptic plasticity. Although the role of N-methyl-D-aspartate (NMDA) receptors in the induction of LTP is well established, the nature of the persistent signal underlying this synaptic enhancement is unclear. Involvement of protein phosphorylation in LTP has been widely proposed, with protein kinase C (PKC) and calcium-calmodulin kinase type II (CaMKII) as leading candidates. Here we test whether the persistent signal in LTP is an enduring phosphoester bond, a long-lived kinase activator, or a constitutively active protein kinase by using H-7, which inhibits activated protein kinases and sphingosine, which competes with activators of PKC (ref. 17) and CaMKII (ref. 18). H-7 suppressed established LTP, indicating that the synaptic potentiation is sustained by persistent protein kinase activity rather than a stably phosphorylated substrate. In contrast, sphingosine did not inhibit established LTP, although it was effective when applied before tetanic stimulation. This suggests that persistent kinase activity is not maintained by a long-lived activator, but is effectively constitutive. Surprisingly, the H-7 block of LTP was reversible; evidently, the kinase directly underlying LTP remains activated even though its catalytic activity is interrupted indicating that such kinase activity does not sustain itself simply through continual autophosphorylation (see refs 9, 13, 15).

    View details for Web of Science ID A1988Q634600059

    View details for PubMedID 2847049

  • MULTIPLE TYPES OF NEURONAL CALCIUM CHANNELS AND THEIR SELECTIVE MODULATION TRENDS IN NEUROSCIENCES Tsien, R. W., Lipscombe, D., Madison, D. V., Bley, K. R., Fox, A. P. 1988; 11 (10): 431-438

    View details for Web of Science ID A1988Q351400005

    View details for PubMedID 2469160

  • IMAGING OF CYTOSOLIC CA-2+ TRANSIENTS ARISING FROM CA-2+ STORES AND CA-2+ CHANNELS IN SYMPATHETIC NEURONS NEURON Lipscombe, D., Madison, D. V., Poenie, M., Reuter, H., Tsien, R. W., Tsien, R. Y. 1988; 1 (5): 355-365

    Abstract

    Changes in cytosolic free Ca2+ concentration [( Ca2+]i) due to Ca2+ entry or Ca2+ release from internal stores were spatially resolved by digital imaging with the Ca2+ indicator fura-2 in frog sympathetic neurons. Electrical stimulation evoked a rise in [Ca2+]i spreading radially from the periphery to the center of the soma. Elevated [K+]o also increased [Ca2+]i, but only in the presence of external Ca2+, indicating that Ca2+ influx through Ca2+ channels is the primary event in the depolarization response. Ca2+ release or uptake from caffeine-sensitive internal stores was able to amplify or attenuate the effects of Ca2+ influx, to generate continued oscillations in [Ca2+]i, and to persistently elevate [Ca2+]i above basal levels after the stores had been Ca2(+)-loaded.

    View details for Web of Science ID A1988P490300002

    View details for PubMedID 2856095

  • ENKEPHALIN HYPERPOLARIZES INTERNEURONES IN THE RAT HIPPOCAMPUS JOURNAL OF PHYSIOLOGY-LONDON Madison, D. V., Nicoll, R. A. 1988; 398: 123-130

    Abstract

    1. Intracellular recordings were made from pyramidal cells and from electrophysiologically identified interneurones in the CA1 region of the hippocampal slice preparation from the rat. 2. Enkephalin blocked the hyperpolarization of pyramidal cells evoked by application of glutamate to synaptically coupled inhibitory interneurones. 3. Enkephalin hyperpolarized interneurones, most probably by increasing potassium conductance; this action was blocked by the opiate antagonist, naloxone. 4. Activation of gamma-aminobutyric acid(B) receptors with baclofen in interneurones produced a similar hyperpolarization that was resistant to naloxone. 5. In addition to hyperpolarizing interneurones, enkephalin blocked the inhibitory postsynaptic potential recorded in these cells. 6. These results suggest that opiate receptors are selectively localized on inhibitory interneurones in the hippocampus and are coupled to potassium channels. Activation of these receptors causes a disinhibition of both pyramidal cells and inhibitory interneurones.

    View details for Web of Science ID A1988M597100009

    View details for PubMedID 3392667

  • SPATIAL-DISTRIBUTION OF CALCIUM CHANNELS AND CYTOSOLIC CALCIUM TRANSIENTS IN GROWTH CONES AND CELL-BODIES OF SYMPATHETIC NEURONS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lipscombe, D., Madison, D. V., Poenie, M., Reuter, H., Tsien, R. Y., Tsien, R. W. 1988; 85 (7): 2398-2402

    Abstract

    Ca2+ imaging and single-channel recording were used to study the regulation of cytosolic free Ca2+ ([Ca2+]i) in local regions of frog sympathetic neurons. Digital imaging with the fluorescent Ca2+ indicator fura-2 demonstrated: (i) resting [Ca2+]i of 70-100 nM; (ii) significant increases in [Ca2+]i in growth cones and cell bodies following depolarization induced by extracellular electrical stimulation or increased external K+; (iii) in cell bodies, large transient increases in [Ca2+]i following exposure to caffeine and sustained oscillations in [Ca2+]i in the presence of elevated K+ and caffeine; and (iv) in growth cones, smaller and briefer changes in [Ca2+]i in response to caffeine. The nature of the depolarization-induced Ca2+ entry was studied with cell-attached patch recordings (110 mM Ba2+ in recording pipette). Ca2+ channel activity was observed in 18 of 20 patches on cell bodies, 3 of 5 patches along neurites, and 36 of 41 patch recordings from growth cones. We observed two types of Ca2+ channels: L-type channels, characterized by a 28-pS slope conductance, sensitivity to dihydropyridine Ca2+ channel agonist, and availability even with depolarizing holding potentials; and N-type channels, characterized by a 15-pS slope conductance, resistance to dihydropyridines, and inactivation with depolarized holding potentials. Both types of channels were found on growth cones and along neurites as well as on cell bodies; channels often appeared concentrated in local hot spots, sometimes dominated by one channel type.

    View details for Web of Science ID A1988M910400082

    View details for PubMedID 2451249

  • NOREPINEPHRINE DECREASES SYNAPTIC INHIBITION IN THE RAT HIPPOCAMPUS BRAIN RESEARCH Madison, D. V., Nicoll, R. A. 1988; 442 (1): 131-138

    Abstract

    The effects of norepinephrine (NE) on inhibitory synaptic potentials were studied on CA1 pyramidal neurons in the hippocampal slice in vitro. Norepinephrine caused the appearance of multiple population spikes in the CA1 region of the hippocampal slice, reminiscent of the actions of gamma-aminobutyric acid (GABA) antagonists. Intracellular recording revealed that NE causes a marked and reversible reduction in inhibitory postsynaptic potentials (IPSPs) recorded in CA1 pyramidal cells. This reduced IPSP results in a larger intracellular excitatory postsynaptic potential (EPSP), which can cause the cell to fire more than one action potential. This disinhibitory effect of NE appears to be mediated by an alpha-receptor, and occurs at a site presynaptic to the pyramidal cell, since NE does not change the reversal potential of the IPSP nor does it affect the amplitude or the reversal potential of iontophoretic GABA responses. In addition to reducing evoked IPSPs, NE causes an increase in the frequency of spontaneous IPSPs, suggesting that inhibition of interneuronal firing may not account for this disinhibitory action of NE.

    View details for Web of Science ID A1988M404600015

    View details for PubMedID 2834010

  • VOLTAGE CLAMP ANALYSIS OF CHOLINERGIC ACTION IN THE HIPPOCAMPUS JOURNAL OF NEUROSCIENCE Madison, D. V., Lancaster, B., Nicoll, R. A. 1987; 7 (3): 733-741

    Abstract

    A slow muscarinic EPSP, accompanied by an increase in membrane input resistance, can be elicited in hippocampal CA1 pyramidal cells in vitro by electrical stimulation of cholinergic afferents in the slice preparation. Associated with the slow EPSP is a blockade of calcium-activated potassium afterhyperpolarizations (AHPs) (Cole and Nicoll, 1984a). In this study a single-electrode voltage clamp was used to examine the currents affected by activation of muscarinic receptors, using either bath application of carbachol or electrical stimulation of the cholinergic afferents. The 3 main findings of this study are that (1) of the 2 calcium-activated potassium currents (termed IAHP and IC) in hippocampal pyramidal cells, only IAHP is sensitive to carbachol; (2) IAHP is approximately 10-fold more sensitive to carbachol than is another muscarine-sensitive current, IM; and (3) neither blockade of IAHP nor of IM can account for the production of the slow EPSP. Rather, the slow EPSP appears to be generated by the blockade of a nonvoltage-dependent, resting potassium current. We propose that the muscarinic blockade of IAHP, which largely accounts for spike frequency adaptation, is primarily involved in enhancing action potential discharge to depolarizing stimuli, while the slow EPSP acts directly to cause action potential discharge.

    View details for Web of Science ID A1987G369400011

    View details for PubMedID 3559710

  • PHORBOL ESTERS BLOCK A VOLTAGE-SENSITIVE CHLORIDE CURRENT IN HIPPOCAMPAL PYRAMIDAL CELLS NATURE Madison, D. V., Malenka, R. C., Nicoll, R. A. 1986; 321 (6071): 695-697

    Abstract

    The importance of second-messenger systems in controlling the excitability of neurones and other cells, through modulation of voltage- and calcium-dependent ionic conductances, has become increasingly clear. Cyclic AMP, acting via protein kinase A, has been identified as the second messenger for several neurotransmitters, and recent studies have suggested that activation of protein kinase C may have similar modulatory actions on neurones. Calcium and potassium currents have so far been shown to be the major ionic conductances modified by kinase activation. We now report that hippocampal pyramidal cells contain a previously undescribed voltage-dependent chloride current which is active at resting potential and is turned off either by membrane depolarization or by activation of protein kinase C by phorbol esters. We propose that this current may reside predominantly in the cell's dendritic membrane and thereby may regulate dendritic excitability.

    View details for Web of Science ID A1986C726800053

    View details for PubMedID 2423884

  • POTENTIATION OF SYNAPTIC TRANSMISSION IN THE HIPPOCAMPUS BY PHORBOL ESTERS NATURE Malenka, R. C., Madison, D. V., Nicoll, R. A. 1986; 321 (6066): 175-177

    Abstract

    Protein kinase C (PKC), a calcium-dependent phospholipid-sensitive kinase which is selectively activated by phorbol esters, is thought to play an important role in several cellular processes. In mammalian brain PKC is present in high concentrations and has been shown to phosphorylate several substrate phosphoproteins, one of which may be involved in the generation of long-term potentiation (LTP), a long-lasting increase in synaptic efficacy evoked by brief, high-frequency stimulation. Since the hippocampus contains one of the brain's highest levels of binding sites for phorbol esters and is the site where LTP has been most thoroughly characterized, we examined the effects of phorbol esters on hippocampal synaptic transmission and LTP. We found that phorbol esters profoundly potentiate excitatory synaptic transmission in the hippocampus in a manner that appears indistinguishable from LTP. Furthermore, after maximal synaptic enhancement by phorbol esters, LTP can no longer be elicited. Although the site of synaptic enhancement during LTP is not clearly established, phorbol esters appear to potentiate synaptic transmission by acting primarily at a presynaptic locus since changes in the postsynaptic responses to the putative transmitter, glutamate, cannot account for the increased synaptic responses induced by phorbol esters. These findings, in conjunction with previous biochemical studies, raise the possibility that, in mammalian brain, PKC plays a role in controlling the release of neurotransmitter and may be involved in the generation of LTP.

    View details for Web of Science ID A1986C226700060

    View details for PubMedID 3010137

  • ACTIONS OF NORADRENALINE RECORDED INTRACELLULARLY IN RAT HIPPOCAMPAL CA1 PYRAMIDAL NEURONS, INVITRO JOURNAL OF PHYSIOLOGY-LONDON Madison, D. V., Nicoll, R. A. 1986; 372: 221-244

    Abstract

    CA1 pyramidal neurones were studied in rat in vitro hippocampal slices using standard intracellular and single-electrode voltage-clamp recording techniques to examine the actions of noradrenaline (NA). NA had two different effects on the resting membrane potential of pyramidal neurones; either a hyperpolarization accompanied by a decrease in membrane input resistance, or less commonly, a depolarization accompanied by an increase in input resistance. In many cells, both effects, a hyperpolarization followed by a depolarization were observed. The depolarization was mediated by a noradrenergic beta-receptor. The hyperpolarization was more difficult to characterize, but may result from alpha-receptor activation. NA reduced the amplitude and duration of the slow calcium-activated potassium after-hyperpolarization (a.h.p.) that follows depolarization-induced action potentials. This action of NA was mediated by beta 1-noradrenergic receptors. NA, in the presence of tetrodotoxin and tetraethylammonium, reduced the a.h.p. without reducing the size of the calcium action potential which preceded it. This was unlike the action of the calcium channel blocker, cadmium, which reduced the calcium action potential and the a.h.p. in parallel. Furthermore, NA did not reduce the amplitude of calcium or barium currents recorded under voltage clamp after blockade of potassium currents. A functional consequence of this blockade of the calcium-activated a.h.p. was a reduction of the accommodation of action potential discharge such that the excitatory responses of the neurone to depolarizing stimuli, such as glutamate application or current passed through the recording electrode, were enhanced. We conclude that the effects of NA on calcium-activated potassium conductance and on resting membrane potential can interact to increase the signal-to-noise ratio of hippocampal pyramidal neurone responsiveness.

    View details for Web of Science ID A1986A551000014

    View details for PubMedID 2873241

  • CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE MEDIATES BETA-RECEPTOR ACTIONS OF NORADRENALINE IN RAT HIPPOCAMPAL PYRAMIDAL CELLS JOURNAL OF PHYSIOLOGY-LONDON Madison, D. V., Nicoll, R. A. 1986; 372: 245-259

    Abstract

    Intracellular recordings were made from rat hippocampal CA1 pyramidal neurones in the in vitro slice preparation to study the actions of cyclic adenosine 3',5'-monophosphate (cyclic AMP). Application of the membrane permeant analogue of cyclic AMP, 8-Br cyclic AMP caused a small depolarization of the resting membrane potential accompanied by an increase in membrane input resistance and also reduced the amplitude of depolarization-evoked calcium-activated potassium after-hyperpolarizations (a.h.p.s.). 8-Br cyclic AMP reduced calcium-activated a.h.p.s but did not reduce calcium action potentials in these cells. 8-Br cyclic AMP also reduced action potential frequency accommodation. The effects of 8-Br cyclic AMP were not mimicked by cyclic AMP applied extracellularly but were imitated by intracellular injections of cyclic AMP. Activation of the endogenous adenylate cyclase of pyramidal cells either by intracellular injection of the stable guanosine 5'-triphosphate (GTP) analogue guanylyl-imidodiphosphate, or by extracellular application of forskolin, reduced the a.h.p. and accommodation. Reducing phosphodiesterase activity with application of either 3-isobutyl-1-methylxanthine or Ro20-1724 reduced the amplitude of the a.h.p. and potentiated the a.h.p.-blocking action of noradrenaline. Reducing adenylate cyclase activity by application of SQ22,536 slightly increased the amplitude of the (a.h.p.) and reduced the a.h.p.-blocking action of noradrenaline. We conclude that the beta-receptor actions of NA on hippocampal CA1 pyramidal cells are mediated by intracellularly produced cyclic AMP.

    View details for Web of Science ID A1986A551000015

    View details for PubMedID 2425084

  • PHORBOL ESTERS MIMIC SOME CHOLINERGIC ACTIONS IN HIPPOCAMPAL PYRAMIDAL NEURONS JOURNAL OF NEUROSCIENCE Malenka, R. C., Madison, D. V., Andrade, R., Nicoll, R. A. 1986; 6 (2): 475-480

    Abstract

    Muscarinic receptor stimulation in the hippocampus has been associated with inositol phospholipid breakdown. In other systems this leads to the formation of inositol trisphosphate and diacylglycerol, which promotes the activation of protein kinase C. Phorbol esters, which directly activate protein kinase C, exhibit high and specific binding in the hippocampus. This, along with the advantages of the hippocampal slice preparation, including direct pharmacological access to a cell population (CA1 pyramidal cells) having clearly defined muscarinic responses, makes this an ideal preparation to examine whether protein kinase C serves as the intracellular signal for muscarinic receptor occupation. Like muscarinic agonists, phorbol esters abolish the slow calcium-activated potassium afterhyperpolarizing potential (AHP) and its underlying current without reducing calcium action potentials. Those phorbol analogs that do not activate kinase C have no effect, suggesting that activation of this enzyme is required to reduce the AHP. The accommodation of spike discharge normally seen during a long depolarizing stimulus is also markedly reduced by phorbol esters as well as by muscarinic receptor activation. However, unlike muscarinic agonists, phorbol esters have no effect on the muscarine-sensitive, voltage-dependent, potassium current termed IM, nor do they consistently cause an increase in input resistance. Moreover, unlike ACh, they do not appear to have a presynaptic inhibitory action on the fast EPSP elicited by orthodromic stimulation. The slow cholinergic EPSP was blocked by phorbol esters, but this could be accounted for by a postsynaptic action. Thus, if inositol phospholipid turnover is involved in mediating muscarinic responses in the hippocampus, the activation of protein kinase C can account for only part of the electrophysiological response.

    View details for Web of Science ID A1986A567900017

    View details for PubMedID 3456434

  • FOLIC-ACID HAS A DIS-INHIBITORY ACTION IN THE RAT HIPPOCAMPAL SLICE PREPARATION BRAIN RESEARCH OTIS, L. C., Madison, D. V., Nicoll, R. A. 1985; 346 (2): 281-286

    Abstract

    The effects of folic acid on synaptic transmission in the hippocampal slice have been studied. Application of folic acid (0.1-1 mM) increased the size of population spikes recorded extracellularly in the CAl pyramidal cell layer and caused the appearance of multiple population spikes. Intracellular recording revealed that folic acid had no consistent effect on the membrane potential, but greatly reduced the rapid chloride-mediated phase of the inhibitory postsynaptic potential (IPSP) evoked by ortho- and antidromic stimulation. The slower, potassium-mediated phase of the IPSP was usually enhanced. Furthermore, folic acid abolished spontaneous IPSPs recorded with potassium chloride-filled microelectrodes. All of these effects were quickly reversible when the drug was washed from the chamber. Finally bath-applied folic acid reduced the hyperpolarization produced by iontophoretically applied GABA. Based on these results, we conclude that folic acid produces its excitatory effects on hippocampal pyramidal cells by a disinhibitory action which involves a postsynaptic blockade of GABA responses.

    View details for Web of Science ID A1985AUA7800006

    View details for PubMedID 2996706

  • CONTROL OF THE REPETITIVE DISCHARGE OF RAT CA1 PYRAMIDAL NEURONS INVITRO JOURNAL OF PHYSIOLOGY-LONDON Madison, D. V., Nicoll, R. A. 1984; 354 (SEP): 319-331

    Abstract

    Experiments using intracellular recording techniques were performed on rat hippocampal neurones in vitro, to study the discharge properties of these cells. When CA 1 pyramidal cells were excited by injecting long depolarizing current pulses (approximately 600-800 ms), they responded with an initial rapid action potential discharge which slowed, or accommodated, and then stopped after 200-300 ms. The train of action potentials was followed by a hyperpolarization which was due primarily to calcium-activated potassium conductance (GK(Ca]. The amplitude of this hyperpolarization increased with an increasing number of action potentials in the initial discharge. Blocking the calcium-activated potassium conductance, by injecting EGTA into the cell, by bathing the cell in cadmium, a calcium channel blocker, or by bathing the cell in calcium-free medium, reduced the after-hyperpolarization (a.h.p.) and accommodation such that the frequency of action potential discharge increased and the duration of this discharge was prolonged. Blocking the calcium-activated potassium conductance had a greater effect on discharge frequency later in the action potential train, as late interspike intervals were shortened more than early ones by the application of cadmium or of calcium-free medium. This was presumably because the calcium-activated potassium conductance was more developed later in the train. Accommodation was not completely abolished in the absence of calcium and presence of cadmium, suggesting that other factors, in addition to calcium-activated potassium conductance, contributed to this process. This remaining accommodation was reduced by low doses of carbachol, suggesting that the M-current also plays a role in accommodation. We conclude that accommodation of the action potential discharge of hippocampal pyramidal cells may be regulated by at least two potassium currents: the calcium-activated potassium current and the M-current. Both of these currents are turned on during excitation of the neurone and act in an inhibitory manner on that neurone to limit further action potential discharge.

    View details for Web of Science ID A1984TK50900021

    View details for PubMedID 6434729

  • GENERAL-ANESTHETICS HYPER-POLARIZE NEURONS IN THE VERTEBRATE CENTRAL NERVOUS-SYSTEM SCIENCE Nicoll, R. A., Madison, D. V. 1982; 217 (4564): 1055-1057

    Abstract

    The effect of general anesthetics on frog motoneurons and rat hippocampus pyramidal cells was examined with sucrose gap and intracellular recording, respectively. A number of volatile and intravenous anesthetics directly hyperpolarized the motoneurons. The potency of these agents in hyperpolarizing motoneurons was strongly correlated with their anesthetic potency. While the responses to barbiturates and alpha-chloralose were blocked by gamma-aminobutyric acid antagonists and were dependent on the chloride gradient, the responses to all the other anesthetics tested were generated by a separate mechanism. Intracellular recording from hippocampal pyramidal cells suggested that an increase in potassium conductance accounts for these responses. Such a nonsynaptic action would contribute to the decreased neuronal responsiveness observed for these compounds and thus to their anesthetic action.

    View details for Web of Science ID A1982PE66400034

    View details for PubMedID 7112112

  • NORADRENALINE BLOCKS ACCOMMODATION OF PYRAMIDAL CELL DISCHARGE IN THE HIPPOCAMPUS NATURE Madison, D. V., Nicoll, R. A. 1982; 299 (5884): 636-638

    View details for Web of Science ID A1982PL32400043

    View details for PubMedID 6289127

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