IL-17A in the hippocampus regulates despair-like behaviors via inhibitory synaptic transmission
- Acta Pharmacol Sin. 2026 Jul;47(7):1777-1791. doi: 10.1038/s41401-026-01761-5.
- 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; The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China. [email protected].
- 7. Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402460, China. [email protected].
- 8. 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. [email protected].
- 9. Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402460, China. [email protected].
- 10. Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China. [email protected].
- 11. Chongqing Institute for Brain and Intelligence, Chongqing, 401336, China. [email protected].
- # Contributed equally.
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.
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