Background

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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糖皮质激素受体依赖性星形胶质细胞介导应激脆弱性

背景

重度抑郁症是一种毁灭性的精神疾病，影响着全世界约 17% 的人口。星形胶质细胞功能障碍与其病理生理学有关。创伤经历和压力导致重度抑郁症的发作，但星形胶质细胞如何应对压力却知之甚少。

方法

使用蛋白质印迹分析，我们发现应激脆弱性与抑郁症小鼠模型中星形胶质细胞糖皮质激素受体 (GR) 表达降低有关。我们通过结合行为研究、纤维光度法、生化实验和 RNA 测序方法，进一步研究了星形胶质细胞 GRs 在调节抑郁症中的作用及其潜在机制。

结果

星形胶质细胞中的 GRs 对压力比神经元中的更敏感。星形胶质细胞中 GR 的缺失诱导抑郁样行为，而在内侧前额叶皮层中恢复星形胶质细胞 GR 表达阻止了抑郁样表型。此外，我们发现内侧前额叶皮层中的 GRs 影响星形胶质细胞 Ca ²⁺活性和动态 ATP（腺苷 5'-三磷酸）释放以响应压力。从 GR 缺失小鼠中分离的星形胶质细胞的 RNA 测序确定了 PI3K-Akt（磷酸肌醇 3-激酶-Akt）信号通路，这是星形胶质细胞 GR 介导的 ATP 释放所必需的。

结论

这些发现表明，星形胶质细胞 GRs 在应激反应中发挥重要作用，并且应激受试者中星形胶质细胞 GR 表达的降低会降低 ATP 释放以介导应激脆弱性。