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

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.