少突胶质细胞connexin通道调节谷氨酸稳态在抑郁症中的作用及机制

Changes in glutamatergic signal in the central nervous system are proved to have a central role in depression in recent years, but the knowledge about how the homeostasis of gluatamate is maintained is still limited. According to present research and our previous work, oligodendrocytes (OLs) has a crucial role in regulating glutamate banlance, but the exact pathway remains unclear. As a highly expressed membrane protein in glial cells, connexins (Cxs) in astrocytes (ASTs) have the ability to affect the release and transportation of glutamate. Based on those evidences, we proposed Cxs in OLs could participate in regulating the glutamate homeostasis in depression related brain regions and affect the progress of depression. By applying cell/brain slices patch clamp, glutamate uptake and other techniques, we sought to examine the role of oligodendroglial Cxs in glutamate transportation in physical conditions. Meanwhile, by combining mice depression model, conditional knockout mice, behavioral tests and electrophysiology methods, we will observe the alternation of oligodendroglial Cxs in depression model and explore the mechanisms underlying the Cx change induced glutamate unbanlance. We hope our study will reveal the function of oligodendroglial Cxs in regulating glutamate homeostasis in depression related brain regions, which may provide a new insight into the pathological mechanisms of depression.

中枢神经系统谷氨酸稳态失衡近年来被认为是抑郁症发病的关键点，但目前我们对谷氨酸稳态调控的认识仍不全面。根据文献和我们的前期研究，少突胶质细胞对谷氨酸代谢和稳态维持具有重要作用，但具体的调控途径并不清楚。作为在胶质细胞中高表达的膜蛋白，connexin (Cx)已被证实在星形胶质细胞中具有对谷氨酸释放和转运的调控作用。本课题从少突胶质细胞中的Cx为切入点，提出“少突胶质细胞通过Cx通道参与调控中枢神经系统抑郁相关脑区的谷氨酸信号，影响抑郁症发病过程”的研究设想。拟通过细胞/脑片膜片钳，谷氨酸摄取等技术明确生理条件下OL中Cx对谷氨酸的转运功能。同时，利用小鼠抑郁模型，条件敲基因小鼠，行为学和电生理等技术，解析抑郁疾病过程中OL中Cx的改变，以及Cx蛋白影响谷氨酸稳态的可能机制。期望阐明OL在抑郁症相关脑区对谷氨酸稳态的维持作用，为抑郁症疾病的发病机制提供新的认知视角。

本课题从少突胶质细胞和髓鞘为切入点，探讨髓鞘在抑郁症等神经精神疾病发病中的作用及机制。结果如下：（1）建立抑郁小鼠模型，发现大脑髓鞘出现脑区差异化增多（2）抗精神病药物Fluoxetine、Risperidone以及Sertraline物可改善CRS模型小鼠抑郁样和焦虑样行为异常，逆转髓鞘异常。（3）星形胶质细胞Cx43通过半通道在髓鞘损伤后通过促进炎症发生抑制髓鞘修复。（4）作为另一种影响精神和认知的疾病模型，我们也采用了慢性酒精中毒模型，发现慢性酒精摄入可抑制OPC分化而抑制成年小鼠髓鞘新生。以上结果对Cx介导的胶质网络在髓鞘再生中的作用做出重要阐述，对髓鞘在神经精神疾病中的作用提供了重要基础数据，为申请者下一步精准解析脑区差异性、神经元差异性髓鞘改变在神经精神疾病中的作用打下良好基础。以上结果目前发表SCI论著两篇，综述一篇，参加国际学术会议交流一次，国内会议交流两次，参与培养博士研究生一名。