title: Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
abstract: Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects produced by the neuroligin-3 R451C-knockin but not the neuroligin-3 knockout mutation, both mutations dramatically impaired tonic but not phasic endocannabinoid signaling. Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA. foldy@stanford.edu
authors.forename: Csaba
authors.initials: C
authors.lastname: Földy
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D059330:GABAergic Neurons / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D063388:Endocannabinoids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C098004:neuroligin 3; D002766:Cholecystokinin