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.
摘要:
突触功能障碍是精神分裂症病理生理学的核心组成部分。然而,与突触功能障碍相关的遗传危险因素和分子机制尚不完全清楚。Stonin2(STON2)基因编码突触小泡的网格蛋白介导的内吞作用(CME)的主要衔接子。在这项研究中,我们发现STON2的C-C(307Pro-851Ala)单倍型增加了精神分裂症的易感性,并检查了STON2变异是否通过CME的调节引起精神分裂症样行为.我们发现与精神分裂症相关的STON2变异导致蛋白质去磷酸化,这影响了它与突触蛋白1(Syt1)的相互作用,一种位于突触前膜中的钙传感器蛋白,对CME至关重要。STON2307Pro851Ala敲入小鼠表现出突触传递缺陷,短期可塑性,和类似精神分裂症的行为。此外,在七种抗精神病药物中,C(307Pro-851Ala)单倍型患者对氟哌啶醇的反应优于T-A(307Ser-851Ser)携带者.通过急性施用氟哌啶醇恢复Syt1分选和突触传递缺陷可有效改善STON2307Pro851Ala敲入小鼠的精神分裂症样行为。我们的发现证明了精神分裂症相关的STON2变异通过调节CME对突触功能障碍的影响,这可能是治疗精神分裂症样表型的有吸引力的治疗靶点。