Extracellular vesicle-based bumetanide delivery alleviates depression-like behaviors of male mice by restoring chloride homeostasis

  • Mol Ther. 2026 Feb 4;34(2):1119-1137. doi: 10.1016/j.ymthe.2025.10.045.
Yang Zhao  1 ,  Wen-Long Xie  1 ,  Yang Liu  2 ,  Jin-Gang He  2 ,  Jian-Guo Chen  3 ,  Fang Wang  4
Affiliations
  • 1. Department of Pharmacology, School of Basic Medicine, Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2. Department of Pharmacology, School of Basic Medicine, Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3. Department of Pharmacology, School of Basic Medicine, Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China; Hubei Shizhen Laboratory, Wuhan 430030, China. Electronic address: [email protected].
  • 4. Department of Pharmacology, School of Basic Medicine, Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China. Electronic address: [email protected].
PMID: 41137395 DOI: 10.1016/j.ymthe.2025.10.045
Abstract

Major depressive disorder (MDD), the most prevalent psychiatric disorder worldwide, is often linked to changes in GABAergic neurotransmission. K+/Cl- cotransporter 2 (KCC2) plays a key role in maintaining proper chloride levels within neurons, influencing the hyperpolarization caused by GABAA receptor (GABAAR) 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 miniature inhibitory postsynaptic currents (mIPSCs). Knockdown of KCC2 expression increased the susceptibility to stress in mice. Conversely, overexpression of KCC2 or treatment with bumetanide reversed the chronic social defeat stress (CSDS)-induced changes in EGABA and deficits of GABAergic neurotransmission, contributing to the improvement of depression-like behaviors. Additionally, extracellular vesicles (EVs) derived from bumetanide-treated HEK293T cells and engineered with acetylcholine receptor (AChR)-specific rabies virus glycoprotein (RVG) peptides, when injected via the tail vein, were found to alleviate depression symptoms. These results suggest that KCC2-mediated chloride homeostasis plays a key role in depression pathology and that bumetanide can be used to treat depression.

Keywords
E(GABA); KCC2; RVG; bumetanide; chloride; depression; extracellular vesicles.
Products