Hippocampal CD39/ENTPD1 promotes mouse depression‐like behavior through hydrolyzing extracellular ATP

Emerging evidence implicates that low levels of ATP in the extracellular space may contribute to the pathophysiology of major depressive disorder (MDD). The concentration of extracellular ATP is regulated by its hydrolase ectonucleotide tri(di)phosphohydrolase (ENTPD). However, the role of ENTPD in depression remains poorly understood. Here we examine the role of CD39 (known as ENTPD1) in mouse depression‐like behavior induced by chronic social defeat stress (CSDS). We demonstrate that CSDS enhances the expression and activity of CD39 in hippocampus. The CD39 functional analog apyrase also induces depression‐like behavior, which can be ameliorated by ATP replenishment. Pharmacological inhibition and genetic silencing of CD39 has an antidepressant‐like effect via increasing hippocampal extracellular ATP concentration, accompanied with an increase in hippocampal neurogenesis and dendritic spine numbers in defeated mice. These results suggest that hippocampal CD39 contributes to CSDS‐induced depression‐like behavior via hydrolyzing extracellular ATP, indicating that CD39 may be a promising new target for the treatment of depression. Synopsis The hippocampal ATP hydrolase CD39 contributes to chronic social defeat stress‐induced depression‐like behavior via hydrolyzing extracellular ATP, suggesting that CD39 may be a potential target for the treatment of depression. CD39 expression and activity are increased by chronic social defeat stress (CSDS) in mice. The CD39 analog apyrase induces depression‐like behaviors of mice. Pharmacological inhibition and knockdown of CD39 have antidepressant‐like effects, promote hippocampal neurogenesis and prevent stubby spine loss by CSDS. Graphical Abstract The hippocampal ATP hydrolase CD39 contributes to chronic social defeat stress‐induced depression‐like behavior via hydrolyzing extracellular ATP, suggesting that CD39 may be a potential target for the treatment of depression.