Pannexin-1 channel dysfunction in the medial prefrontal cortex mediates depressive-like behaviors in mice

抄録

BACKGROUND: Pannexin-1 (Panx1) is a new gap junction channel that mainly distributes in the brain and mediates the releases of adenosine triphosphate (ATP). Mefloquine has been widely reported to induce depressive symptoms and is also known as a broad-spectrum Panx1 inhibitor. Recent studies have reported that exogenous ATP infusion has a potential antidepressant-like effect, it remains poorly understood whether the Panx1 channel participates in pathophysiology of depression. Here, we aimed to investigate whether Panx1 function is associated with CSDS-elicited depressive-like behaviors and the psychiatric side effects of mefloquine.

METHODS: We measured Panx1 and Panx1-P2X7 receptors (P2X7R) complex expression and function in the CSDS model. We also injected mice with Panx1 inhibitors and measured their depressive-like and anxiety behaviors. To assess the role of Panx1 in the psychiatric side effects of mefloquine, we examined the function of Panx1 and depressive-like and anxiety behaviors after administration of mefloquine.

RESULTS: We found that CSDS reduced Panx1 expression and function in the medial prefrontal cortex (mPFC), accompanied by a deficit of Panx1-P2X7R complex. Pharmacological blockage of Panx1 in mPFC with CBX or 10Panx were sufficient to induce depressive-like behaviors and an increased vulnerability to stress in mice, which were prevented by preconditioning with ATP. Finally, systemic and intral-mPFC injection of mefloquine both inhibited the function of Panx1, meanwhile, they induced depressive-like and anxiety behaviors in mice with sub-threshold social defeat stress.

CONCLUSIONS: Our results suggest that the Panx1 channel in the mPFC contributes to the chronic stress and mefloquine-induced depressive-like and anxiety behaviors.

Keywords: Pannexin-1, Mefloquine, Depression

Disclosures: The authors declare that they have no conflicts of interest to session attendees.