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.

中文翻译：

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海马 CD39/ENTPD1 通过水解细胞外 ATP 促进小鼠抑郁样行为。

新出现的证据表明，细胞外空间中低水平的 ATP 可能有助于重度抑郁症 (MDD) 的病理生理学。细胞外 ATP 的浓度受其水解酶外核苷酸三（二）磷酸水解酶 (ENTPD) 的调节。然而，ENTPD 在抑郁症中的作用仍然知之甚少。在这里，我们研究了 CD39（称为 ENTPD1）在由慢性社交失败压力（CSDS）诱导的小鼠抑郁样行为中的作用。我们证明 CSDS 增强了海马中 CD39 的表达和活性。CD39 功能类似物腺苷三磷酸双磷酸酶也诱导抑郁样行为，这可以通过 ATP 补充来改善。CD39的药理抑制和基因沉默通过增加海马细胞外ATP浓度具有抗抑郁样作用，伴随着被击败的小鼠海马神经发生和树突棘数量的增加。这些结果表明，海马 CD39 通过水解细胞外 ATP 促进 CSDS 诱导的抑郁样行为，表明 CD39 可能是治疗抑郁症的有希望的新靶点。