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Cell. 2014 Jul 3;158(1):198-212. doi: 10.1016/j.cell.2014.04.045.

Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.

Author information

1
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.
2
Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA.
3
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA.
4
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
5
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA. Electronic address: malenka@stanford.edu.
6
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.

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.

PMID:
24995986
PMCID:
PMC4120877
DOI:
10.1016/j.cell.2014.04.045
[Indexed for MEDLINE]
Free PMC Article

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