{Reference Type}: Journal Article
{Title}: STON2 variations are involved in synaptic dysfunction and schizophrenia-like behaviors by regulating Syt1 trafficking.
{Author}: Ma Y;Gao K;Sun X;Wang J;Yang Y;Wu J;Chai A;Yao L;Liu N;Yu H;Su Y;Lu T;Wang L;Yue W;Zhang X;Xu L;Zhang D;Li J;
{Journal}: Sci Bull (Beijing)
{Volume}: 69
{Issue}: 10
{Year}: 2024 May 30
{Factor}: 20.577
{DOI}: 10.1016/j.scib.2024.02.013
{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 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.