水通道蛋白4调节星形胶质细胞功能及其与抑郁症的相关性

已经阐明星形胶质细胞谷氨酸循环障碍和营养支持功能下降在抑郁症的病理进程中发挥着重要作用。申请者前期研究发现水通道蛋白4（Aquaporin-4，AQP4）调节星形胶质细胞谷氨酸重摄取和神经营养功能，可能与抑郁症相关。本项目拟应用AQP4敲除和星形胶质细胞AQP4条件敲除小鼠，在整体、细胞和分子水平系统研究AQP4对星形胶质细胞介导的谷氨酸循环和脑源性神经生长因子（BDNF）平衡的调节作用及其在抑郁症病理进程中的作用。预期研究结果将揭示AQP4与抑郁症发生发展的相关性，为基于星形胶质细胞功能调节发展抗抑郁治疗新策略和研发新型抗抑郁药提供重要靶标。

Major depressive disorder (MDD) has been associated with astroglial dysfunction, but the underlying mechanisms have remained elusive. Aquaporin-4 (AQP4) is the main aquaporin in the brain and is expressed in highest density in the perivascular and subpial astrocyte end-feet. Our previous studies showed that AQP4 was an essential mediator for regulating glutamate uptake, and AQP4 knockout abolished fluoxetine-induced enhancement of hippocampal neurogenesis and antidepressant effects. Thus, we suppose that AQP4 may be involved in the MDD via regulating the functions of astrocytes. This study is designed to investigate the role of AQP4 in the pathogenesis of MDD, and related possible biological mechanism. Here, using AQP4 knockout and astroglia-conditional knockout mice, we will establish chronic mild stress (CMS)-induced anhedonia model of depression. After evaluating depression-like behaviors in different genotype mice with or without treatment of fluoxetine, we will focus the effects of AQP4 on the glutamate recycle and the balance of brain-derived neurotrophic factor (BDNF) and proBDNF during the MDD. These findings will demonstrate that AQP4 is involved in astrocytic pathology during the development of MDD throught glutamate recycle and BDNF balance, and indicate that AQP4 may be a therapeutic target for novel and more effective anti-depressant treatments.