STON2风险变异通过影响Syt1转运和突触功能导致精神分裂症样行为  

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

作　　者：马远林 高凯 孙晓璇 王金鑫 杨扬 武建荧 柴安平 姚立 刘楠 郁昊 苏怡 卢天兰 王力芳 岳伟华 章晓辉 徐林 张岱 李俊 Yuanlin Ma;Kai Gao;Xiaoxuan Sun;Jinxin Wang;Yang Yang;Jianying Wu;Anping Chai;Li Yao;Nan Liu;Hao Yu;Yi Su;Tianlan Lu;Lifang Wang;Weihua Yue;Xiaohui Zhang;Lin Xu;Dai Zhang;Jun Li(Peking University Sixth Hospital,Peking University Institute of Mental Health,NHC Key Laboratory of Mental Health(Peking University),National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital),Key Laboratory of Mental Health,Chinese Academy of Medical Sciences,Beijing 100191,China;The First Affiliated Hospital,Chongqing Medical University,Chongqing Key Laboratory of Neurology,Chongqing 400016,China;Changping Laboratory,Beijing 102206,China;d Chinese Institute for Brain Research,Beijing 102206,China;Laboratory of Learning and Memory,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650201,China;Shenzhen Key Laboratory of Translational Research for Brain Diseases,The Brain Cognition and Brain Disease Institute,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions,Shenzhen 518055,China;State Key Laboratory of Cognitive Neuroscience and Learning,IDG/McGovern Institute for Brain Research,Beijing Normal University,Beijing 100875,China;PKU-IDG/McGovern Institute for Brain Research,Peking University,Beijing 100871,China)

机构地区：[1]Peking University Sixth Hospital,Peking University Institute of Mental Health,NHC Key Laboratory of Mental Health(Peking University),National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital),Key Laboratory of Mental Health,Chinese Academy of Medical Sciences,Beijing 100191,China [2]The First Affiliated Hospital,Chongqing Medical University,Chongqing Key Laboratory of Neurology,Chongqing 400016,China [3]Changping Laboratory,Beijing 102206,China [4]d Chinese Institute for Brain Research,Beijing 102206,China [5]Laboratory of Learning and Memory,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650201,China [6]Shenzhen Key Laboratory of Translational Research for Brain Diseases,The Brain Cognition and Brain Disease Institute,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions,Shenzhen 518055,China [7]State Key Laboratory of Cognitive Neuroscience and Learning,IDG/McGovern Institute for Brain Research,Beijing Normal University,Beijing 100875,China [8]PKU-IDG/McGovern Institute for Brain Research,Peking University,Beijing 100871,China

出　　处：《Science Bulletin》2024年第10期1458-1471,共14页科学通报（英文版）

基　　金：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);the Non-profit Central Research Institute Chinese Academy of Medical Sciences(2023-PT320-08).

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.

关 键 词：STON2 variations SCHIZOPHRENIA Synaptic dysfunction Syt1 HALOPERIDOL 

分 类 号：R749.3[医药卫生—神经病学与精神病学]