Differential Alterations in Striatal Direct and Indirect Pathways Mediate Two Autism-like Behaviors in Valproate-Exposed Mice

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent stud-ies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration. Concurrent altera-tion in indirect pathway was a depressed state of basal activity, with enhancement in transient responsiveness of D2-MSNs during repetitive behaviors. A causal relationship linking such differential alterations in these two pathways to the coexistence of these two autism-like behaviors was demonstrated by the cell type-specific correction of abnormal basal activity in the D1-MSNs and D2-MSNs of valproate-exposed mice. The findings support those differential alterations in two striatal path-ways mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing ther-apeutic options targeting these circuit alterations.

Automated summary

Autism is characterized by social deficits and repetitive behaviors. Recent studies have shown differential alterations in the ventral and dorsal striatum, and this study revealed coexisting and opposite morphologic and functional changes in the dorsostriatal direct and indirect pathways. These changes are responsible for the two different autism-like behaviors exhibited by male mice prenatally exposed to valproate. This finding supports the notion that differential alterations in striatal pathways mediate the coexistence of social deficits and repetitive behaviors in autism.