Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, Shaanxi 710062, China.
College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
J Neurosci. 2022 Oct 12;42(41):7833-7847. doi: 10.1523/JNEUROSCI.0623-22.2022. Epub 2022 Sep 6.
Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies 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 alteration 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 pathways mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations. Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although a number of recent studies have implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, but social behaviors need to be processed by a series of actions, and repetitive behaviors, especially the high-order repetitive behaviors such as restrictive interests, have its scope to cognitive and emotional domains. The current study, for the first time, revealed that prenatal valproate exposure induced coexisting and differential alterations in the dorsomedial striatal direct and indirect pathways, and that these alterations mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations to address the behavioral abnormalities.
自闭症的两个关键诊断标准包括社交缺陷和重复行为。虽然最近的一些研究表明腹侧纹状体与社交缺陷有关，背侧纹状体与重复行为有关，但社交行为需要通过一系列的动作来处理，而重复行为，特别是限制兴趣等高级重复行为，其范围涉及认知和情感领域。本研究首次揭示，丙戊酸钠暴露导致内侧纹状体直接和间接通路共存且存在差异，这些改变分别介导了两种共存的自闭症样行为异常。这一结果有助于开发针对这些回路改变的治疗方法，以解决行为异常问题。
