精神分裂症(面向对象编程)
神经传递
突触蛋白1
神经科学
突触可塑性
氟哌啶醇
突触小泡
医学
生物
精神科
遗传学
多巴胺
受体
小泡
膜
作者
Yuanlin Ma,Kai Gao,Xiaoxuan Sun,Jinxin Wang,Yongrong Yang,Jianying Wu,Anping Chai,Yao Li,Nan Li,Hao Yu,Yi Su,Tianlan Lu,Lifang Wang,Weihua Yue,Xiaohui Zhang,Lin Xu,Dai Zhang,Jun Li
标识
DOI:10.1016/j.scib.2024.02.013
摘要
Synaptic dysfunction is a core component of the pathophysiology of schizophrenia. However, the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood. The Stonin 2 (STON2) gene encodes a major adaptor for clathrin-mediated endocytosis (CME) of synaptic vesicles. In this study, we showed that the C-C (307Pro-851Ala) haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME. We found that schizophrenia-related STON2 variations led to protein dephosphorylation, which affected its interaction with synaptotagmin 1 (Syt1), a calcium sensor protein located in the presynaptic membrane that is critical for CME. STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission, short-term plasticity, and schizophrenia-like behaviors. Moreover, among seven antipsychotic drugs, patients with the C-C (307Pro-851Ala) haplotype responded better to haloperidol than did the T-A (307Ser-851Ser) carriers. The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice. Our findings demonstrated the effect of schizophrenia-related STON2 variations on synaptic dysfunction through the regulation of CME, which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.
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