title: Neuroligins Are Selectively Essential for NMDAR Signaling in Cerebellar Stellate Interneurons.
abstract: Neuroligins are postsynaptic cell-adhesion molecules that contribute to synapse specification. However, many other postsynaptic cell-adhesion molecules are known and the relative contributions of neuroligins versus other such molecules in different types of synapses and neurons remains largely unknown. Here, we have studied the role of neuroligins in cerebellar stellate interneurons that participate in a well defined circuit that converges on Purkinje cells as the major output neurons of cerebellar cortex. By crossing triple conditional knock-out (cKO) mice targeting all three major neuroligins [neuroligin-1 to neuroligin-3 (NL123)] with parvalbumin-Cre (PV-Cre) transgenic mice, we deleted neuroligins from inhibitory cerebellar interneurons and Purkinje cells, allowing us to study the effects of neuroligin deletions on cerebellar stellate cell synapses by electrophysiology in acute slices. PV-Cre/NL123 cKO mice did not exhibit gross alterations of cerebellar structure or cerebellar interneuron morphology. Strikingly, electrophysiological recordings in stellate cells from these PV-Cre/NL123 cKO mice revealed a large decrease in NMDAR-mediated excitatory synaptic responses, which, in stellate cells, are largely extrasynaptic, without a change in AMPA-receptor-mediated responses. Parallel analyses in PV-Cre/NL1 mice that are single NL1 cKO mice uncovered the same phenotype, demonstrating that NL1 is responsible for recruiting extrasynaptic NMDARs. Moreover, we observed only a modest impairment in inhibitory synaptic responses in stellate cells lacking NL123 despite a nearly complete suppression of inhibitory synaptic transmission in Purkinje cells by the same genetic manipulation. Our results suggest that, unlike other types of neurons investigated, neuroligins are selectively essential in cerebellar stellate interneurons for enabling the function of extrasynaptic NMDARs.
  
  
  
  Neuroligins are postsynaptic cell-adhesion molecules genetically linked to autism. However, the contributions of neuroligins to interneuron functions remain largely unknown. Here, we analyzed the role of neuroligins in cerebellar stellate interneurons. We deleted neuroligin-1, neuroligin-2, and neuroligin-3, the major cerebellar neuroligin isoforms, from stellate cells in triple NL123 conditional knock-out mice and analyzed synaptic responses by acute slice electrophysiology. We find that neuroligins are selectively essential for extrasynaptic NMDAR-mediated signaling, but dispensable for both AMPAR-mediated and inhibitory synaptic transmission. Our results reveal a critical and selective role for neuroligins in the regulation of NMDAR responses in cerebellar stellate interneurons.
authors: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305 zbo@stanford.edu.
authors: Bo
authors: 0000-0003-2451-0593
authors: B
authors: Zhang
authors: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305.
authors: Thomas C
authors: TC
authors: Südhof
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D018709:Statistics, Nonparametric; D013331:Strychnine / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D015816:Cell Adhesion Molecules, Neuronal; D018683:Excitatory Amino Acid Agents; D018756:GABA Antagonists; D018684:Glycine Agents; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D010852:Picrotoxin; D016194:Receptors, N-Methyl-D-Aspartate; D013331:Strychnine; C093438:neuroligin 1; C098003:neuroligin 2; C098004:neuroligin 3; C054562:yellow fluorescent protein, Bacteria
keywords: cerebellum; neuroligin; stellate cell; synaptic transmission