We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP⁺-Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.

中文翻译：

---

星形胶质谷氨酸交换子xCT在腹侧海马中对压力的抵抗力中的作用。

我们证明，压力差异调节谷氨酸稳态的背侧和腹侧海马，并确定星形胶质xCT在腹侧齿状回（vDG）中在应激和抗抑郁反应中的作用。我们为压力敏感型vDG提供了RNA-seq路线图。转录因子REST与表观遗传标记H3K27ac共同与xCT启动子结合，以调节xCT的表达，这在固有的对抑郁样行为的易感性的遗传小鼠模型中也降低了。在药理学上，用乙酰基L-肉碱（LAC）或乙酰基N-半胱氨酸（NAC）调节组蛋白乙酰化迅速增加xCT并激活具有mGlu2受体的网络以引发增强的谷氨酸稳态，从而促进促弹性和抗抑郁样反应。 。药理学xCT阻滞抵消了NAC的预防作用。玻璃纤维增​​强纤维⁺在VDG模拟物在促进弹性药理作用XCT的-Cre依赖性过表达。这项工作建立了一种机制，通过该机制，vDG保护可通过xCT-mGlu2网络的表观遗传程序编程导致应激弹性和抗抑郁反应。