Theranostics 2022; 12(8):3703-3718. doi:10.7150/thno.72144 This issue

Research Paper

P2X2 receptors in pyramidal neurons are critical for regulating vulnerability to chronic stress

Xiao-Jing Kuang1#, Can-Yuan Zhang1#, Bing-Yi Yan1, Wei-Zhong Cai1, Cheng-Lin Lu1, Li-Jia Xie1, Shu-Ji Li1, Peng-Li Kong1, Jun Fan1, Shu-Min Pan1, Ting Guo1, Xiong Cao1,2✉

1. Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, P. R. China.
2. Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Kuang XJ, Zhang CY, Yan BY, Cai WZ, Lu CL, Xie LJ, Li SJ, Kong PL, Fan J, Pan SM, Guo T, Cao X. P2X2 receptors in pyramidal neurons are critical for regulating vulnerability to chronic stress. Theranostics 2022; 12(8):3703-3718. doi:10.7150/thno.72144. Available from

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Graphic abstract

Rationale: Stress is a major risk factor for the development of depression. However, the underlying molecular mechanisms of stress vulnerability in depression are largely uncharacterized.

Methods: P2X2 receptors (a major receptor for gliotransmitter-ATP) in the medial prefrontal cortex (mPFC) were identified by real-time qPCR, western blots and RNAscope in situ hybridization in chronic social defeat stress model (CSDS). We generated P2X2 conditional knockout mice and overexpressed AAV-P2X2 in CamkIIα-Cre mice. The depression-like behaviors were assessed via CSDS, subthreshold social defeat stress (SSDS), social interaction test (SI), forced interaction test (FIT), forced swimming test (FST), sucrose preference test (SPT), novel stressed feeding (NSF) and open field test (OFT). The neuronal activity and synapse function of P2X2 receptors in the mPFC were detected by in vivo fiber-photometry, patch-clamp techniques and neuronal morphometric analysis.

Results: We identified that P2X2 receptors were increased in the mPFC of susceptible mice in CSDS. Conditional knockout of P2X2 receptors in pyramidal neurons promoted resilience of chronic stress-induced depressive-like behaviors, whereas pyramidal neurons - specific gain of P2X2 in the mPFC increased vulnerability to depressive-like behaviors. In vivo fiber-photometry, electrophysiology and neuronal morphometric analysis showed P2X2 receptors regulated neuronal activity and synapse function in the mPFC.

Conclusions: Overall, our studies reveal a critical role of P2X2 in mediating vulnerability to chronic stress and identify P2X2 as a potential therapeutic target for treatment of stress-related mood disorders.

Keywords: P2X2 receptors, stress vulnerability, mPFC, chronic stress, synapse