<i>STON2</i> variations are involved in synaptic dysfunction and schizophrenia-like behaviors by regulating Syt1 trafficking

作者全名：Ma, Yuanlin; Gao, Kai; Sun, Xiaoxuan; Wang, Jinxin; Yang, Yang; Wu, Jianying; Chai, Anping; Yao, Li; Liu, Nan; Yu, Hao; Su, Yi; Lu, Tianlan; Wang, Lifang; Yue, Weihua; Zhang, Xiaohui; Xu, Lin; Zhang, Dai; Li, Jun

作者地址：[Ma, Yuanlin; Gao, Kai; Sun, Xiaoxuan; Yang, Yang; Yu, Hao; Su, Yi; Lu, Tianlan; Wang, Lifang; Yue, Weihua; Zhang, Dai; Li, Jun] Peking Univ, Peking Univ Inst Mental Hlth, NHC Key Lab Mental Hlth,Key Lab Mental Hlth, Natl Clin Res Ctr Mental Disorders,Hosp 6, Beijing 100191, Peoples R China; [Ma, Yuanlin] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China; [Gao, Kai; Zhang, Dai; Li, Jun] Changping Lab, Beijing 102206, Peoples R China; [Wang, Jinxin; Wu, Jianying] Chinese Inst Brain Res, Beijing 102206, Peoples R China; [Chai, Anping; Xu, Lin] Chinese Acad Sci, Kunming Inst Zool, Lab Learning & Memory, Kunming 650223, Peoples R China; [Chai, Anping] Chinese Acad Sci, Shenzhen Hong Kong Inst Brain Sci Shenzhen Fundame, Shenzhen Key Lab Translat Res Brain Dis,Brain Cogn, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China; [Yao, Li; Liu, Nan; Zhang, Xiaohui] Beijing Normal Univ, IDG McGovern Inst Brain Res, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China; [Yue, Weihua] Peking Univ, PKU IDG McGovern Inst Brain Res, Beijing 100871, Peoples R China

通信作者：Li, J (通讯作者)，Peking Univ, Peking Univ Inst Mental Hlth, NHC Key Lab Mental Hlth,Key Lab Mental Hlth, Natl Clin Res Ctr Mental Disorders,Hosp 6, Beijing 100191, Peoples R China.; Li, J (通讯作者)，Changping Lab, Beijing 102206, Peoples R China.

来源：SCIENCE BULLETIN

ESI学科分类：Multidisciplinary

WOS号：WOS:001246290000001

JCR分区：Q1

影响因子：18.8

年份：2024

卷号：69

期号：10

开始页：1458

结束页：1471

文献类型：Article

关键词：STON2 variations; Schizophrenia; Synaptic dysfunction; Syt1; Haloperidol

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 schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME, which might be attractive therapeutic targets for treating schizophrenia -like phenotypes. (c) 2024 Science China Press. Published by Elsevier B.V. and Science China Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

基金机构：Key Realm R&D Program of Guangdong Province [2019B030335001]; National Natural Science Foundation of China [82330042, 81825009, 82071541, 81971283, 82271576, 82101570]; Changping Laboratory [2021B-01-01]; China Postdoctoral Science Foundation [2021M690421]; Non-profit Central Research Institute Chinese Academy of Medical Sciences [2023-PT320-08]

基金资助正文：This work was supported by the Key Realm R&D Program of Guangdong Province (2019B030335001), the National Natural Science Foundation of China (82330042, 81825009, 82071541, 81971283, 82271576, and 82101570), Changping Laboratory (2021B-01-01), the China Postdoctoral Science Foundation (2021M690421), and the Non-profit Central Research Institute Chinese Academy of Medical Sciences (2023-PT320-08).