Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism.
Neuroligins are postsynaptic cell-adhesion molecules implicated in autism and other neuropsychiatric disorders. Despite extensive work, the role of neuroligins in synapse function and plasticity, especially N-methyl-d-aspartate (NMDA) receptor (NMDAR)-dependent long-term potentiation (LTP), remains unclear. To establish which synaptic functions unequivocally require neuroligins, we analyzed single and triple conditional knockout (cKO) mice for all three major neuroligin isoforms (NL1-NL3). We inactivated neuroligins by stereotactic viral expression of Cre-recombinase in hippocampal CA1 region pyramidal neurons at postnatal day 0 (P0) or day 21 (P21) and measured synaptic function, synaptic plasticity and spine numbers in acute hippocampal slices 2-3 weeks later. Surprisingly, we find that ablation of neuroligins in newborn or juvenile mice only modestly impaired basal synaptic function in hippocampus and caused no alteration in postsynaptic spine numbers. However, triple cKO of NL1-NL3 or single cKO of NL1 impaired NMDAR-mediated excitatory postsynaptic currents and abolished NMDAR-dependent LTP. Strikingly, the NL1 cKO also abolished LTP elicited by activation of L-type Ca(2+)-channels during blockade of NMDARs. These findings demonstrate that neuroligins are generally not essential for synapse formation in CA1 pyramidal neurons but shape synaptic properties and that NL1 specifically is required for LTP induced by postsynaptic Ca(2+)-elevations, a function which may contribute to the pathophysiological role of neuroligins in brain disorders.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.80.
View details for DOI 10.1038/mp.2016.80
View details for PubMedID 27217145
Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion
2015; 161 (4): 803-816
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
View details for PubMedID 25913192
View details for PubMedCentralID PMC4447122
Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens.
2014; 345 (6196): 535-542
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 2014; 345 (6196): 535-542
A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of A on synapses and dendritic spines
HUMAN MOLECULAR GENETICS
2012; 21 (6): 1384-1390
Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in the elderly. Accumulating evidence supports soluble amyloid-β (Aβ) oligomers as the leading candidate for the causative agent in AD and synapses as the primary site of Aβ oligomer action. However, the molecular and cellular mechanisms by which Aβ oligomers cause synaptic dysfunction and cognitive impairments remain poorly understood. Using primary cultures of rat hippocampal neurons as a model system, we show that the partitioning defective-1 (PAR-1)/microtubule affinity-regulating kinase (MARK) family kinases act as critical mediators of Aβ toxicity on synapses and dendritic spines. Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. Our results reveal a critical role for PAR-1/MARK kinases in AD pathogenesis and suggest PAR-1/MARK inhibitors as potential therapeutics for AD and possibly other tauopathies where aberrant tau hyperphosphorylation is involved.
View details for DOI 10.1093/hmg/ddr576
View details for Web of Science ID 000300721300015
View details for PubMedID 22156579
Postsynaptic Complexin Controls AMPA Receptor Exocytosis during LTP
2012; 73 (2): 260-267
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
Interneurons in the basolateral amygdala
2011; 60 (5): 765-773
The amygdala is a temporal lobe structure that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala arises from its role in processing fear and the relationship of fear to human anxiety. The amygdaloid complex is divided into a number of subnuclei that have extensive intra and extra nuclear connections. In this review we discuss recent findings on the physiology and plasticity of inputs to interneurons in the basolateral amygdala, the primary input station. These interneurons are a heterogeneous group of cells that can be separated on immunohistochemical and electrophysiological grounds. Glutamatergic inputs to these interneurons form diverse types of excitatory synapses. This diversity is manifest in both the subunit composition of the underlying NMDA receptors as well as their ability to show plasticity. We discuss these differences and their relationship to fear learning. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.
View details for DOI 10.1016/j.neuropharm.2010.11.006
View details for Web of Science ID 000289316600008
View details for PubMedID 21093462
A Specific Class of Interneuron Mediates Inhibitory Plasticity in the Lateral Amygdala
JOURNAL OF NEUROSCIENCE
2010; 30 (44): 14619-14629
The lateral amygdala (LA) plays a key role in emotional learning and is the main site for sensory input into the amygdala. Within the LA, pyramidal neurons comprise the major cell population with plasticity of inputs to these neurons thought to underlie fear learning. Pyramidal neuron activity is tightly controlled by local interneurons, and GABAergic modulation strongly influences amygdala-dependent learning. Synaptic inputs to some interneurons in the LA can also undergo synaptic plasticity, but the identity of these cells and the mechanisms that underlie this plasticity are not known. Here we show that long-term potentiation (LTP) in LA interneurons is restricted to a specific type of interneuron that is defined by the lack of expression of synaptic NR2B subunits. We find that LTP is only present at cortical inputs to these cells and is initiated by calcium influx via calcium-permeable AMPA receptors. LTP is maintained by trafficking of GluR2-lacking AMPA receptors that require an interaction with SAP97 and the actin cytoskeleton. Our results define a novel population of interneurons in the LA that control principal neuron excitability by feed-forward inhibition of cortical origin. This selective enhanced inhibition may contribute to reducing the activity of principal neurons engaged during extinction of conditioned fear.
View details for DOI 10.1523/JNEUROSCI.3252-10.2010
View details for Web of Science ID 000283793400004
View details for PubMedID 21048119
A class III histidine kinase acts as a novel virulence factor in Botrytis cinerea
MOLECULAR PLANT-MICROBE INTERACTIONS
2006; 19 (9): 1042-1050
Filamentous ascomycetes contain large numbers of histidine kinases (HK) that belong to eleven classes. Members of class III from different species were previously shown to be involved in osmoregulation and resistance to dicarboximide and phenylpyrrole fungicides. We have inactivated the gene encoding the single group III HK, BOS1, in the economically important plant pathogen Botrytis cinerea. BOS1 inactivation had pleiotropic effects on the fungus. Besides the expected osmosensitivity and resistance to fungicides, null mutants presented additional characteristics indicating that BOS1 is necessary for normal macroconidiation and full virulence. On standard culture media, null mutants very rarely formed conidiophores and those few conidiophores failed to produce conidia. This defect could be partially restored with 1 M sorbitol, suggesting that another BOS1-independent signal cascade may be involved in macroconidiation. The mutants were not found to be hypersensitive to various oxidative stresses but were more resistant to menadione. Finally, pathogenicity tests showed that bos1-null mutants were significantly reduced in the ability to infect host plants. Appressorium morphogenesis was not altered; however, in planta growth was severely reduced. To our knowledge, this is the first class III HK characterized as a pathogenicity factor in a plant-pathogenic ascomycete.
View details for DOI 10.1094/MPMI-19-1042
View details for Web of Science ID 000239850000011
View details for PubMedID 16941908
Phylogenetic analysis of Pinguicula (Lentibulariaceae): Chloroplast DNA sequences and morphology support several geographically distinct radiations
AMERICAN JOURNAL OF BOTANY
2005; 92 (10): 1723-1736
The genus Pinguicula is one of the three genera of the carnivorous Lentibulariaceae, comprising approximately 80 species. Phylogeny inference using nucleotide sequences of the chloroplast gene matK and the trnK group II intron, as well as a set of 32 morphological characters revealed five well-supported, major lineages within the genus. These lineages largely reflect radiations in clearly defined geographic regions, whereas most previously recognized sections of the genus are shown to be para- or polyphyletic. A species-rich Mexican-Central American-Caribbean clade has the Eurasian P. alpina and an East Asian clade as successive sisters. All three are characterized by a production of flower buds on winter-resting plants, a specific corolla hair structure and a very large corolla lower central lobe. Another diverse clade is composed of species with primarily European distribution including the widespread type species P. vulgaris. For this clade, vegetative reproduction during dormancy is synapomorphic. Species native to SE North America and the South American Andes and a group of Mediterranean and NE Atlantic coast species together appear in a fifth well-supported clade, that is characterized by a tropical-type growth habit. It is the only clade that has reached temperate zones of the southern hemisphere.
View details for Web of Science ID 000232356800014
View details for PubMedID 21646090