title: Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
abstract: In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Rothwell
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Marc V
authors.initials: MV
authors.lastname: Fuccillo
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Maxeiner
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hayton
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Ozgun
authors.initials: O
authors.lastname: Gokce
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Byung Kook
authors.initials: BK
authors.lastname: Lim
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Fowler
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA. Electronic address: malenka@stanford.edu.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA. Electronic address: tcs1@stanford.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D001479:Basal Ganglia / Q000378:metabolism / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism; D045442:Rotarod Performance Test
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C098004:neuroligin 3