Mus musculus Raw sequence reads
Patients with autism spectrum disorder (ASD) often exhibit dysregulated microglia and innate immune responses. However, the underlying mechanisms of microglia-evoked neuroinflammation in the development of ASD phenotypes have not been elucidated. Recent research has proposed that alarmin S100A9 is implicated in the pathophysiology of ASD. The aim of this study was to investigate the role and underlying mechanisms of microglial S100A9 in ASD phenotypes. We utilized the BTBR T+ tf/J (BTBR) mouse, a reliable preclinical model for ASD, showing core behavioral features of ASD as well as persistent immune dysregulation. Significant overexpression of microglial S100A9 was observed in the hippocampus of BTBR mice. The social dysfunction was attenuated by a pharmacological inhibitor of S100A9, paralleled by a significant reduction in activated microglia morphological phenotype, inflammatory receptors, and proinflammatory cytokines. Notably, S100A9 inhibition reversed the reactive neuronal activity and promoted myelination in the CA3 subregion of BTBR mice. Furthermore, the promyelinating compound administration ameliorated the ASD-relevant behaviors in BTBR mice. Collectively, these findings indicate that microglia-derived S100A9 induces the neuroinflammation cascade, myelination deficits, and social dysfunction. Targeting microglial S100A9 in the hippocampus may be a promising therapeutic strategy for neuroinflammation-related neurodevelopmental disorders.