Astrocyte-derived ATP modulates depressive-like behaviors
Astrocyte-derived ATP modulates depressive-like behaviors
复制标题
星形胶质细胞衍生的 ATP 调节抑郁样行为
DOI：
10.1038/nm.3162
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发表时间：
2013-06-01
期刊：
影响因子：
82.9
通讯作者：
Gao, Tian-Ming
中科院分区：
文献类型：
--
作者：
Cao, Xiong;Li, Liang-Ping;Gao, Tian-Ming
重度抑郁症（MDD）是一种导致残疾的疾病，影响着全球约16%的人口（1）；然而，对于这种疾病的潜在生物学机制知之甚少。对抑郁症患者的动物研究、死后大脑分析以及影像学研究都表明神经胶质功能障碍在MDD病理生理学中起作用（2 - 7）。然而，星形胶质细胞调节抑郁行为的分子机制在很大程度上尚未明确。在此，我们确定ATP是成年小鼠中星形胶质细胞调节抑郁样行为的一个关键因素。我们观察到在易受慢性社交挫败影响的小鼠大脑中ATP含量较低。此外，我们发现给予ATP可在这些小鼠中诱导出快速的抗抑郁样效应。缺乏2型肌醇1,4,5 - 三磷酸受体以及囊泡胶质传递的转基因阻断都会导致星形胶质细胞ATP释放不足，从而引起抑郁样行为，而这种行为可通过给予ATP来挽救。利用仅在星形胶质细胞中表达G(q) G蛋白偶联受体的转基因小鼠来选择性激活星形胶质细胞的Ca2+信号，我们发现刺激星形胶质细胞内源性ATP释放可在抑郁症小鼠模型中诱导出抗抑郁样效应。此外，我们发现内侧前额叶皮质中的P2X2受体介导了ATP的抗抑郁样效应。这些结果突显了星形胶质细胞ATP释放是MDD的一种生物学机制。
Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology,,,,,. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a GqG protein–coupled receptor only in astrocytes to enable selective activation of astrocytic Ca2+signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.