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

Patrick E. Rothwell, Marc V. Fuccillo, Stephan Maxeiner, Scott J. Hayton, Ozgun Gokce, Byung Kook Lim, Stephen C. Fowler, Robert C. Malenka, Thomas C. Südhof

Research output: Contribution to journalArticlepeer-review

209 Scopus citations


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. PaperFlick.

Original languageEnglish (US)
Pages (from-to)198-212
Number of pages15
Issue number1
StatePublished - Jul 3 2014

Bibliographical note

Funding Information:
We thank A. Darvishzadeh, A. Afjei, G. Sun, S. Ghosh, and N. Huang for technical assistance, C. Földy for advice, and all Malenka and Südhof lab members for helpful discussions. This work was supported by grants from the NIMH (P50 MH086403 to R.C.M. and T.C.S., K99 MH099243 to M.V.F., and F32 MH096491 to P.E.R.); initial stages were also supported by the Simons Foundation (to R.C.M. and T.C.S.).

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