补体C3激活依赖的突触靶向异常修剪在抑郁症中的作用及机制

临床研究表明，突触缺失和功能异常与抑郁症发生紧密相关，小胶质细胞可在补体成分的引导下对活性较低或多余的突触进行靶向修剪，维持中枢神经系统的稳态发育和正常功能。本课题组前期预实验发现，应激敏感小鼠mPFC区小胶质细胞激活，激活的小胶质细胞吞噬兴奋性突触，血清和mPFC区补体C3表达增加，给予C3抑制剂可减轻小鼠对应激的敏感性。因此本课题提出，抑郁症发病过程中补体C3信号通路异常激活，小胶质细胞通过自身表达的补体受体识别标记到突触上的补体C3，继而靶向吞噬该突触，导致突触缺失和功能受损，从而参与抑郁症的发生发展。本项目拟通过建立离体脑片和整体动物模型，特异性调控补体C3信号通路，探讨补体C3激活介导的小胶质细胞对成熟突触靶向异常修剪在抑郁症中的作用及机制，阐明抑郁症发生的生物学基础，揭示固有免疫系统在抑郁症中的作用及机制，为抑郁症及其他心境障碍性疾病防治研究提供新思路。

Numerous clinical studies have demonstrated that synaptic loss and dysfunction are closely related to major depressive disorders. Previous studies have shown that synaptic pruning by microglia is important for the development and function of central nervous system. Our preliminary experiments found that the microglia was activated and engulfed the excitatory synapse in the medial prefrontal cortex of stress-susceptible mice, and the level of C3 was significantly increased. In addition, C3 inhibitor could decrease the susceptibility of mice to chronic stress. Therefore, we hypothesized that the over-activity of complement component C3 activation would evoke the abnormal targeted pruning of mature synapse by microglia, resulted in synaptic loss and depressive-like behavior. In this study, the in vitro and in vivo models will be employed. The effects of complement C3 activation on synapse-targeted pruning by microglia will be investigated. It is helpful to understand the role and underlying mechanism of the abnormalities of complement C3 activation in major depressive disorders. Our study will provide new target and strategy for the treatment of major depressive disorders and other affective disorders.