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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.

SUBMITTER: Rothwell PE 

PROVIDER: S-EPMC4120877 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Rothwell Patrick E PE   Fuccillo Marc V MV   Maxeiner Stephan S   Hayton Scott J SJ   Gokce Ozgun O   Lim Byung Kook BK   Fowler Stephen C SC   Malenka Robert C RC   Südhof Thomas C TC  

Cell 20140701 1


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 repetitiv  ...[more]

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