<p>Extracellular adenosine triphosphate (ATP) dysregulation has been implicated in the pathogenesis of major depressive disorder. However, the mechanisms underlying ATP deficiency in the medial prefrontal cortex (mPFC) under stress conditions remain unclear. Here, we found that only stress-susceptible mice exhibited deficiencies in both the basal ATP levels and reward task-evoked ATP release, and these deficits could be reversed by treatment with fluoxetine. We also observed specific downregulation of Slc17a9, a gene encoding the vesicular nucleotide transporter (VNUT), in the mPFC of stress-susceptible mice. Conditional knockout of Slc17a9 in neurons (n-cKO), but not in astrocytes was sufficient to induce depressive-like behaviors following subthreshold social defeat stress (SSDS), accompanied by decreased basal extracellular ATP levels and impaired reward-evoked ATP release in the mPFC. Similar deficits were reproduced by specific knockdown of Slc17a9 in BLA^{mPFC-projecting} neurons. Notably, these behavioral deficits were reversed by microinjection of the nonhydrolyzable ATP analogs (ATPγS) into the mPFC. Furthermore, we demonstrated that the BLA-mPFC pathway bidirectionally regulated depressive-like behaviors via ATP release following SSDS. Overall, our study provides evidence that ATP release modulates susceptibility to social stress in a circuit-specific manner and highlights the essential role of stress-induced ATP deficiency in the pathogenesis of depression.</p>