Extracellular vesicles-mediated delivery of bumetanide alleviates depressive-like behaviors of male mice via restoring chloride homeostasis

Mol Ther. 2025 Oct 23:S1525-0016(25)00866-4. doi: 10.1016/j.ymthe.2025.10.045. Online ahead of print.

ABSTRACT

Major depressive disorder (MDD), which is the most prevalent psychiatric disorder worldwide, is often linked to changes in GABAergic neurotransmission. The potassium-chloride cotransporter 2 (KCC2) plays a key role in maintaining proper chloride levels within neurons, influencing the hyperpolarization caused by GABA_AR activation in mature neurons. However, the impact of KCC2-modulated GABAergic neurotransmission on depressive behaviors remains unclear. In this study, we investigated the role of KCC2 in a mouse model of depression. Our findings revealed a significant decrease in KCC2 expression in the dorsal hippocampus (dHip), accompanied by a depolarizing shift of the GABA reverse potential and a reduction in the amplitude of mIPSCs. Knockdown of KCC2 expression increased the susceptibility to stress of mice. Conversely, overexpression of KCC2 or treatment with bumetanide reversed the chronic social defeat stress (CSDS)-induced changes in E_GABA and deficits of GABAergic neurotransmission, contributing to the improvement of depressive-like behaviors. Additionally, extracellular vesicles (EVs) derived from bumetanide-treated HEK-293T cells and engineered with acetylcholine receptor (AChR)-specific rabies virus glycoprotein (RVG) peptides, when injected via the tail vein, were found to alleviate depressive symptoms. These results suggest that KCC2-mediated chloride homeostasis plays a key role in depression pathology and bumetanide can be used to treat depression.

PMID:41137395 | DOI:10.1016/j.ymthe.2025.10.045