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Cerebellar microglia-derived IL-17A mitigates autism-related behavioral and synaptic deficits
Jun Yin1, Wei Li1, Li-Ping Shen1,2
1State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, Department of Anesthesiology, Nanjing Drum Tower Hospital, Institute for Brain Sciences, and Department of Physiology and AI Biology, School of Life Sciences, Nanjing University, Nanjing, China.
None:
Interleukin-17 (IL-17) is a pleiotropic cytokine produced mainly by peripheral T helper 17 cells. Yet, the brain functions of IL-17 derived from central nervous cells remain poorly understood. Here, we find an aberrant IL-17A signaling in the cerebellum of Fmr1-KO mice, a well-established genetic model for autism spectrum disorder (ASD). Cerebellar IL-17A, derived exclusively from microglia, is essential for the regulation of social behaviors by maintaining neuronal excitability and selectively suppressing inhibitory neurotransmission of Purkinje cells (PCs) in the cerebellar Crus I, a brain region critically involved in social cognition. Specific downregulation of IL-17 receptor-mediated signaling in cerebellar PCs recapitulates ASD-like social deficits and repetitive behaviors. Notably, both direct administration of IL-17A and induction of IL-17A release from cerebellar microglia by poly(I:C) effectively restore PC excitability and ameliorate ASD-like symptoms. The findings uncover an indispensable role of microglia-derived IL-17A for cerebellar social processing and suggest potential therapeutic strategies targeting IL-17A signaling for ASD.
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