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Cerebellar microglia-derived IL-17A compensates for autism-related deficits [purified cerebellar microglia]

ABSTRACT: Interleukin-17 (IL-17) is a pleiotropic cytokine produced mainly by peripheral Th17 cells. Yet, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE287705 | GEO | 2026/02/03

REPOSITORIES: GEO

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Cerebellar microglia-derived IL-17A compensates for autism-related deficits [cerebellar crus 1]

Project description:Interleukin-17 (IL-17) is a pleiotropic cytokine produced mainly by peripheral Th17 cells. Yet, 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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Cerebellar microglia-derived IL-17A compensates for autism-related deficits [purified cerebellar microglia]

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