抗抑郁新药靶的研究进展

摘要：

Major depressive disorder (MDD) affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder and there is an urgent need for novel therapeutic targets for MDD. Our previous study identified ATP as a key factor involved in astrocytic modulation of depressive-like behaviors and found a fast antidepressant-like effect of ATP administration on a couples of mouse model of depression. Recently, by examining the expression level of various extracellular ATP hydrolase from different brain regions after chronic stress, we observed an increased expression of Entpd1/CD39, a microglia-derived ATP hydrolase, in the mPFC of depressed mice. Pharmacological and genetic manipulations demonstrated that this enzyme was also involved in modulating depressive-like behaviors by degrading ATP. Thereafter, we explored the cellular and neural circuit mechanisms underlying ATP modulation of these behaviors and observed that deficiency of extracellular ATP led to both reduced GABAergic inhibition and elevated excitability in lateral habenula (LHb)-projecting, but not dorsal raphe (DRN)-projecting, mPFC neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of LHb-projecting mPFC neurons and regulated depressive-like behaviors. Remarkably, chemogenetic activation of the mPFC-LHb pathway induced depressive-like behaviors in naive mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairments in depressed mice. Overall, our study indicates that the extracellular ATP level in the mPFC controlled by both astrocyte secretion and microglia-derived ATP hydrolase modulate depressive-like behaviors via mPFC-LHb circuit and these findings may provide novel therapeutic targets for MDD.

代表性论文：

1. Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013 Jun;19(6):773-7.

2. Chen YH, Lin S, Jin SY, Gao TM. Extracellular ATP Is a Homeostatic Messenger That Mediates Cell-Cell Communication in Physiological Processes and Psychiatric Diseases. Biol Psychiatry. 2025 Jan 1;97(1):41-53.

3. Wu JL, Li ZM, Chen H, Chen WJ, Hu NY, Jin SY, Li XW, Chen YH, Yang JM, Gao TM. Distinct septo-hippocampal cholinergic projections separately mediate stress-induced emotional and cognitive deficits. Sci Adv. 2024 Nov 8;10(45):eado1508.