Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors
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Issue Date
2014-07-03Author
Fuccillo, Marc V.
Rothwell, Patrick E.
Maxeiner, Stephan
Hayton, Scott J.
Gokce, Ozgun
Lim, Byung Kook
Fowler, Stephen C.
Malenka, Robert C.
Sudhof, Thomas C.
Publisher
Elsevier
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Metadata
Show full item recordAbstract
In humans, neuroligin-3 mutations are associated with autism, while 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.
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Citation
Rothwell, Patrick E., Marc V. Fuccillo, Stephan Maxeiner, Scott J. Hayton, Ozgun Gokce, Byung Kook Lim, Stephen C. Fowler, Robert C. Malenka, and Thomas C. Sudhof. "Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors." Cell 158.1 (2014): 198-212.
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