Article

IL-17A in the hippocampus regulates despair-like behaviors via inhibitory synaptic transmission

Yue Wang1, He-ming Yu1, Yong He1, Jun-chao Cai1, Yu Tian2, Xiang-yu Chen1, Qing-yuan Wu1,3, Ti-fei Yuan4, An-mu Xie5, Yi Guo6,7,8, Ke Cheng9, Peng Xie1,9,10,11
1 Department of Neurology, NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
2 Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin 300052, China
3 Department of Neurology, Chongqing University Three Gorges Hospital, Chongqing 404000, China
4 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
5 Neurology Department, the Affiliated Hospital of Qingdao University, Qingdao 266000, China
6 Department of Neurology, Shenzhen People’s Hospital
7 The Second Clinical Medical College, Jinan University
8 The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020 Guangdong, China
9 Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402460, China
10 Chongqing Key Laboratory of Neurobiology, Chongqing 400016, China
11 Chongqing Institute for Brain and Intelligence, Chongqing 401336, China
Correspondence to: Yi Guo: xuanyi_guo@163.com, Ke Cheng: jackchengke@163.com, Peng Xie: xiepeng@cqmu.edu.cn,
DOI: 10.1038/s41401-026-01761-5
Received: 20 November 2024
Accepted: 25 January 2026
Advance online: 17 March 2026

Abstract

Neuroinflammation plays an important role in the pathophysiology of depression. Interleukin-17A (IL-17A), an inflammatory cytokine, is strongly associated with depression; however, the potential mechanisms through which IL-17A in the brain regulates depressive symptoms remain unknown. Our study aimed at finding out the potential pathway through which IL-17A in the brain regulates depressive-like behaviours. Anti-despair-like behaviours, an important index for evaluating depression in mice, are present in IL-17A knockout mice. Given that the hippocampus is a brain region that is implicated in depression, the level of IL-17A in the hippocampus was evaluated in chronic unpredictable mild stress (CUMS) mice, and the results revealed increased hippocampal IL-17A levels. The expression of IL-17A was subsequently regulated by the stereotactic injection of multivesicular liposomes loaded with IL-17A recombinant protein as a sustained release system, and the AAV-il17a or AAV-shRNA(il17a) into the hippocampus. IL-17A overexpression induced despair-like behaviour, and the anti-despair-like phenotype in IL-17A knockout mice was blocked by the restoration of IL-17A expression in the hippocampus, which demonstrated the role of IL-17A in depression. Gene microarray, UPLC‒MS/MS, Western blot and patch clamp analyses were used to determine the pathway through which IL-17A regulates despair-like behaviours. Enhanced inhibitory synaptic transmission was detected in IL-17A-knockout mice. Furthermore, reducing the expression of the GABAA receptor α2 subunit (GABRA2) abrogated antidespair-like behaviour in IL-17A knockout mice, and hippocampal GABARA2 overexpression alleviated despair-like behaviour in CUMS mice. These results proved that GABRA2-mediated inhibitory synaptic transmission participated in the regulation of depressive-like behaviours by IL-17A. Our results revealed a vital role for IL-17A in depression and suggested that GABRA2 is the key molecule involved in the regulation of depression by IL-17A, indicating its potential as a therapeutic target for depression.
Keywords: depression; inflammation; GABA receptors

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