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

PE Rothwell, MV Fuccillo, S Maxeiner, SJ Hayton… - Cell, 2014 - cell.com
PE Rothwell, MV Fuccillo, S Maxeiner, SJ Hayton, O Gokce, BK Lim, SC Fowler…
Cell, 2014cell.com
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 …
Summary
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.
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