title: Astrocyte-derived ATP modulates depressive-like behaviors.
abstract: 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 Gq 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.
authors: Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors: Xiong
authors: X
authors: Cao
authors: Liang-Ping
authors: LP
authors: Li
authors: Qian
authors: Q
authors: Wang
authors: Qiong
authors: Q
authors: Wu
authors: Hong-Hai
authors: HH
authors: Hu
authors: Meng
authors: M
authors: Zhang
authors: Ying-Ying
authors: YY
authors: Fang
authors: Jie
authors: J
authors: Zhang
authors: Shu-Ji
authors: SJ
authors: Li
authors: Wen-Chao
authors: WC
authors: Xiong
authors: Hua-Cheng
authors: HC
authors: Yan
authors: Yu-Bo
authors: YB
authors: Gao
authors: Ji-Hong
authors: JH
authors: Liu
authors: Xiao-Wen
authors: XW
authors: Li
authors: Li-Rong
authors: LR
authors: Sun
authors: Yuan-Ning
authors: YN
authors: Zeng
authors: Xin-Hong
authors: XH
authors: Zhu
authors: Tian-Ming
authors: TM
authors: Gao
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D003865:Major Depressive Disorder / Q000209:etiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000502:physiology; D058476:Receptors, Purinergic P2X2 / Q000502:physiology; D050600:SNARE Proteins / Q000502:physiology
chemical_list: C506927:ITPR2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C470191:MrgA1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D058476:Receptors, Purinergic P2X2; D050600:SNARE Proteins; D000255:Adenosine Triphosphate
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