Abstract
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.
基金项目
Key Realm Research and Development Program of Guangdong Province(2019B030335001)
国家自然科学基金(82330042)
国家自然科学基金(81825009)
国家自然科学基金(82071541)
国家自然科学基金(81971283)
国家自然科学基金(82271576)
国家自然科学基金(82101570)
Changping Laboratory(2021B-01-01)
中国博士后科学基金(2021M690421)
Nonprofit Central Research Institute Chinese Academy of Medical Sciences(2023-PT320-08)
NETL
NSTL
万方数据