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. Histopathological postmortem studies have con¬sistently shown reductions in glial cell density and numbers in the prefrontal cortex in individuals with MDD. Additionally, a microarray-based investigation demonstrated dysregulation of genes involved in ATP biosynthesis and use in the PFC in subjects with MDD. Previous animal studies have also implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are uncharacterized. Using behavioral models of depression and genetic approaches, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. It was observed that low ATP abundance in the brains of mice that were susceptible to chronic social defeat, a model that mimics several psychopathological dimensions of depression. Furthermore, 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 Ca2+ signaling, researchers found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, P2X2 receptor was found in the medial prefrontal cortex to mediate the antidepressant-like effects of ATP. In addition, we found that ATP is necessary and sufficient for astrocytes to promote adult hippocampal neurogenesis, which is casually related to MDD. These results highlight the role of astrocytes modulating the emotion, such as depression, and the astrocytic ATP signaling will be a novel drug target for fast-acting antidepressant.