Astrocyte-derived ATP modulates depressive-like behaviors

• Published in: Nature medicine Vol. 19; no. 6; pp. 773 - 777
• Main Authors: Cao, Xiong, Li, Liang-Ping, Wang, Qian, Wu, Qiong, Hu, Hong-Hai, Zhang, Meng, Fang, Ying-Ying, Zhang, Jie, Li, Shu-Ji, Xiong, Wen-Chao, Yan, Hua-Cheng, Gao, Yu-Bo, Liu, Ji-Hong, Li, Xiao-Wen, Sun, Li-Rong, Zeng, Yuan-Ning, Zhu, Xin-Hong, Gao, Tian-Ming
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2013; Nature Publishing Group
• Subjects: 631/378/1689/1414; Adenosine triphosphatase; Adenosine triphosphate; Adenosine Triphosphate - physiology; Animals; Astrocytes; Astrocytes - physiology; ATP; Behavior; Biomedicine; Brain research; Cancer Research; Depressive Disorder, Major - etiology; Development and progression; Genetic aspects; Infectious Diseases; Inositol 1,4,5-Trisphosphate Receptors - physiology; letter; Major depressive disorder; Male; Mental depression; Metabolic Diseases; Mice; Mice, Inbred C57BL; Molecular Medicine; Neurosciences; Physiological aspects; Prefrontal Cortex - physiology; Receptors, G-Protein-Coupled - analysis; Receptors, G-Protein-Coupled - physiology; Receptors, Purinergic P2X2 - physiology; SNARE Proteins - physiology; China
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3162

Astrocytic dysfunction is a common feature in the brains of depressed subjects. Now, Xin-Hong Zhu and colleagues show that astrocytic release of ATP is reduced in the brains of stressed mice and that restoring brain ATP levels can rapidly reverse depressed behaviors in mice. Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population 1 ; 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 2 , 3 , 4 , 5 , 6 , 7 . 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 G q G protein–coupled receptor only in astrocytes to enable selective activation of astrocytic Ca 2+ 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.