Potentiation of nigra-striatal dopaminergic projection underpins core autism-like behaviors in valproate-exposed mice

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. However, the underlying neural circuit dysfunction that accounts for these coexisting symptoms in autism remains poorly understood. Here we revealed that prenatal valproate exposure induced functional alterations of dopaminergic projections from substantia nigra pars compacta (SNc) to dorsomedial striatum (DMS). Specifically, we observed enhanced excitatory input and increased excitability in SNc-DMS dopamine (DA) neurons, resulting in a basal state of potentiation. This potentiated baseline activity blunted the phasic responses of SNc-DMS projections, as evidenced by reduction of transient Ca 2+ and DA signaling during social interaction and expression of repetitive behaviors in valproate-exposed male mice. We then utilized chronic chemogenetic and optogenetic approaches to selectively manipulate the abnormal basal activity of SNc-DMS dopaminergic signaling. This targeted intervention successfully rectified the dysfunction in D1R expressed medium spiny neurons (D1-MSNs) associated with social deficits, while simultaneously restoring the functionality of D2-MSNs linked to repetitive behaviors. Collectively, our findings support the hypothesis that prenatal valproate exposure disrupts SNc-DMS dopaminergic signaling, which mediates the coexistence of two core autism-like behaviors by reshaping the dynamics of direct and indirect pathway MSNs. Moreover, these results highlight potential therapeutic targets for developing interventions for both core symptoms of autism. Significance statement Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although the two core symptoms are apparently different and seemingly unrelated, they are actually associated each other, social behaviors need to be processed by a series of actions. Repetitive behaviors, especially the high-order restrictive interests, have their scopes to cognitive and emotional domains. This study, for the first time, revealed that prenatal valproate exposure disrupts nigrostriatal dopaminergic signaling, which mediated the coexistence of two core autism-like behaviors by reshaping the dynamics of direct and indirect pathway MSNs. These results offer insights regarding dopaminergic signaling as a hub underpinning the two coexisting behavioral abnormalities, and highlighting potential therapeutic targets for autism.