Stress is a major risk factor for the development of depression. However, the underlying molecular mechanisms of stress vulnerability in depression are largely uncharacterized. P2X2 receptors (a major receptor for gliotransmitter-ATP) in the medial prefrontal cortex (mPFC) were identified by real-time qPCR, western blots and RNAscope hybridization in chronic social defeat stress model (CSDS). We generated P2X2 conditional knockout mice and overexpressed AAV-P2X2 in 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 fiber-photometry, patch-clamp techniques and neuronal morphometric analysis. 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. fiber-photometry, electrophysiology and neuronal morphometric analysis showed P2X2 receptors regulated neuronal activity and synapse function in the mPFC. 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.