Zheng Qi, Zhao Yongsi, Cheng Qiangqiang, Wang Hao, Liu Fuhong, Lai Jingru, Liu Yaqi, Zhang Xinyuan, Kang Yifan, Li Zhongqi, Cao Bing, Wei Chunling, Qian Zhaoqiang, Fan Juan, Ren Wei, Tian Yingfang
College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, Shaanxi 710062, China.
J Neurosci. 2025 Sep 3;45(36):e0382252025. doi: 10.1523/JNEUROSCI.0382-25.2025.
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 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.
自闭症的特征在于两个关键诊断标准，包括社交缺陷和重复行为。然而，导致自闭症中这些共存症状的潜在神经回路功能障碍仍知之甚少。在这里，我们揭示了产前丙戊酸暴露会导致从黑质致密部（SNc）到背内侧纹状体（DMS）的多巴胺能投射发生功能改变。具体而言，我们观察到SNc→DMS多巴胺（DA）神经元的兴奋性输入增强且兴奋性增加，导致一种增强的基础状态。这种增强的基线活动减弱了SNc→DMS投射的相位反应，这在丙戊酸暴露的雄性小鼠的社交互动过程中短暂钙和DA信号的减少以及重复行为的表达中得到了证明。然后，我们利用慢性化学遗传学和光遗传学方法选择性地操纵SNc→DMS多巴胺能信号的异常基础活动。这种有针对性的干预成功纠正了与社交缺陷相关的D1R表达的中等棘状神经元（D1-MSNs）的功能障碍，同时恢复了与重复行为相关的D2-MSNs的功能。总的来说，我们的研究结果支持这样一种假设，即产前丙戊酸暴露会破坏SNc→DMS多巴胺能信号，该信号通过重塑直接和间接通路MSNs的动态来介导两种核心自闭症样行为的共存。此外，这些结果突出了针对自闭症两种核心症状开发干预措施的潜在治疗靶点。
