糖皮质激素受体
星形胶质细胞
前额叶皮质
糖皮质激素
PI3K/AKT/mTOR通路
神经科学
蛋白激酶B
重性抑郁障碍
内分泌学
内科学
细胞生物学
生物
医学
信号转导
中枢神经系统
认知
作者
Chunfeng Lu,Jing Ren,Jianhua Mo,Jun Fan,Fang Guo,Liang-Yü Chen,You-Lu Wen,Shu-Ji Li,Yunxia Fang,Wu Z,Yulong Li,Tianming Gao,Xiong Cao
标识
DOI:10.1016/j.biopsych.2021.11.022
摘要
Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood.Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods.GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release.These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability.
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