Hippocampal CD39/ENTPD1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP
Hippocampal CD39/ENTPD1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP
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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
DOI：
10.15252/embr.201947857
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发表时间：
2020-04-03
期刊：
影响因子：
7.7
通讯作者：
Wang, Fang
中科院分区：
文献类型：
--
作者：
Cui, Qian-Qian;Hu, Zhuang-Li;Wang, Fang
新出现的证据表明，细胞外空间低水平的ATP可能与重度抑郁症（MDD）的病理生理有关。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（被称为ENTPD1）在慢性社会失败应激（CSDS）诱导的小鼠抑郁样行为中的作用。我们证明了CSDS增强了海马中CD39的表达和活性。CD39功能类似磷酸酶也诱导抑郁样行为，这可以通过ATP补充来改善。CD39的药物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，同时在失败小鼠中海马神经发生和树突棘数量增加。这些结果表明，海马CD39通过水解细胞外ATP参与csds诱导的抑郁样行为，表明CD39可能是治疗抑郁症的一个有希望的新靶点。
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.