黏附分子肌营养不良蛋白聚糖介导的GABAA受体功能受损在抑郁症发病机制中的作用研究

临床资料表明，GABAA受体的表达和功能下调与抑郁症的发生发展密切相关。黏附分子肌营养不良蛋白聚糖（dystroglycan，DG）特异性表达于抑制性突触，稳态调节突触后膜GABAA受体水平。我们的预实验发现，抑郁敏感鼠海马脑区α-DG蛋白表达水平较对照组和抵抗组明显减少。因此，本课题提出，在抑郁症发病过程中可能存在海马脑区黏附分子DG信号通路减弱，减少GABAA受体在突触后膜的簇集和定位，使GABAA受体介导的抑制性突触传递受损，参与抑郁症的发生发展。本课题拟通过建立应激的体外模型及整体动物模型，调控DG信号通路不同节点，观察GABAA受体表达、分布及功能改变，探讨海马脑区黏附分子DG信号通路异常在抑郁症中的作用，为抑郁症防治提供新靶点和新策略，为阐明细胞黏附分子在抑郁症中的意义及机制提供实验依据，为其他情感障碍性疾病防治研究提供新思路。

Numerous clinical studies demonstrate that the decrease in expression and function of GABAA receptor are closely related to major depressive disorders. Previous studies show that dystroglycan (DG) specially localized in the inhibitory synapse and regulated the level of GABAA receptor. Our preliminary experiments found that the level of alpha-DG protein in the hippocampus was significantly decreased in the depression-susceptible mice, but not in other brain areas. Therefore, we hypothesized that the decreased activity of DG signaling pathway in hippocampus prevented the synaptic locolization and function of GABAA receptors, resulted in depressive behavior. In this study, the in vitro and in vivo chronic stress models will be employed. The effects of regulation of DG-mediated signaling pathway on the expression, distribution and function of GABAA receptors will be investigated. It is helpful to understand the role and underlying mechanism of the abnormalities of DG signaling pathway in major depressive disorders. Our study will provide new target and strategy for the treatment of major depressive disorders and other affective disorders.