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

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

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
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 vesi-cles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the suscepti-bility 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 attrac-tive therapeutic targets for treating schizophrenia-like phenotypes.

STON2 variationsSchizophreniaSynaptic dysfunctionSyt1Haloperidol

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

展开 >

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

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-IDC/McGovern Institute for Brain Research,Peking University,Beijing 100871,China

展开 >

Key Realm Research and Development Program of Guangdong Province国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Changping Laboratory中国博士后科学基金Nonprofit Central Research Institute Chinese Academy of Medical Sciences

2019B0303350018233004281825009820715418197128382271576821015702021B-01-012021M6904212023-PT320-08

2024

10.1016/j.scib.2024.02.013

科学通报(英文版)
中国科学院

科学通报(英文版)

CSTPCD
ISSN：1001-6538
年,卷(期)：2024.69(10)
  • 65