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.

Pannexin-1 channel dysfunction in the medial prefrontal cortex mediates depressive-like behaviors induced by chronic social defeat stress and administration of mefloquine in mice.

Mefloquine (MFQ) is widely used for the treatment of malaria clinically. Apart from antimalarial effect, psychiatric side effects such as depression and anxiety of MFQ have been reported. Interestingly, MFQ is also known as a broad-spectrum pannexin-1 (Panx1) inhibitor. Panx1 is a new gap junction channel in the brain which mediates efflux of adenosine triphosphate (ATP). Although exogenous ATP has been known to produce a potential antidepressant-like effect, little is known about the role of Panx1 in pathophysiology of depression, especially the depression induced by administration of MFQ. Here, we used the chronic social defeat stress (CSDS) model and found a decrease in the expression and function of Panx1 in the medial prefrontal cortex (mPFC) of susceptible mice. Furthermore, pharmacological blockade of Panx1 in the mPFC with carbenoxolone (CBX) (100 mM) or 10Panx (100 µM) was sufficient to induce depressive-like behaviors and increase vulnerability to stress in mice, which were prevented by preconditioning with ATP (25 µM). Finally, systemic and intral-mPFC injection of MFQ both inhibited the activity of Panx1 and induced depressive-like and anxiety behaviors in mice with sub-threshold social defeat stress. Indeed, the behavioral abnormalities induced by MFQ were prevented by preconditioning with ATP in the mPFC. In conclusion, our study demonstrates a role of the Panx1 channel in chronic stress and MFQ-induced depressive-like and anxiety behaviors, which may provide a novel molecular mechanism for psychiatric side effects of MFQ.

Multiple H+ sensors mediate the extracellular acidification-induced [Ca2+]i elevation in cultured rat ventricular cardiomyocytes.

Acidosis has been known to cause "Ca2+ transients", however, the mechanism is still uncertain. Here, we demonstrated that multiple H+ sensors, such as ASICs, TRPV1 and proton-sensing G protein coupled receptors (GPCRs) are involved in extracellular acidification-induced intracellular calcium ([Ca2+]i) elevation. By using calcium imaging measures, we observed that both ASIC and TRPV1 channels inhibitors suppressed the [Ca2+]i elevation induced by extracellular acidosis in cultured rat cardiac myocytes. Then, both channels mRNA and proteins were identified by RT-PCR, western blotting and immunofluorescence. ASIC-like and TRPV1-like currents were induced by extracellular acidification, suggesting that functional ASIC and TRPV1 channels jointly mediated extracellular calcium entry. Furthermore, either pre-exhaustion of sarcoplasmic reticulum (SR) Ca2+ with thapsigargin or IP3 receptor blocker 2-APB or PLC inhibitor U73122 significantly attenuated the elevation of [Ca2+]i, indicating that the intracellular Ca2+ stores and the PLC-IP3 signaling also contributed to the acidosis-induced elevation of [Ca2+]i. By using genetic and pharmacological approaches, we identified that ovarian cancer G protein-coupled receptor 1 (OGR1) might be another main component in acidosis-induced release of [Ca2+]i. These results suggest that multiple H+-sensitive receptors are involved in "Ca2+ transients" induced by acidosis in the heart.