Work

Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism

Year: 2024

Type: article

Abstract: Growing evidence supports a role for dysregulated neuroinflammation in autism. However, the underlying mechanisms of microglia-evoked neuroinflammation in the development of autistic phenotypes have not been elucidated. This study aimed to investigate the role and underlying mechanisms of microglial S100 calcium-binding protein A9 (S100A9) in autistic phenotypes. We utilized the BTBR T + tf/J (BTBR) mouse, a reliable preclinical model for autism that displays core behavioral features of autism as well as persistent immune dysregulation. A combination of behavioral, pharmacological, immunological, genetic, molecular, and transcriptomics approaches were used to uncover the potential role of S100A9 in autism. Significant overexpression of microglial S100A9 was observed in the hippocampus of BTBR mice. BTBR mice displayed decreased social communication and increased repetitive behaviors compared to C57BL/6 mice. Interestingly, the above social dysfunction was attenuated by a pharmacological inhibitor of S100A9, accompanied by a significant reduction in the activated microglia morphological phenotype, inflammatory receptors, and proinflammatory cytokines. Notably, S100A9 inhibition decreased c-Fos + cells and promoted myelination in the cornu ammonis 3 of BTBR mice. Furthermore, the promyelinating compound administration ameliorated the autism-relevant behaviors in BTBR mice. Our findings indicate that microglia-derived S100A9 triggers the neuroinflammation cascade, myelination deficits, and social dysfunction. Targeting S100A9 could, therefore, be a promising therapeutic strategy for neuroinflammation-related neurodevelopmental disorders. Schematic summary of the proposed mechanism underlying S100A9-mediated neuroinflammation and myelination deficits in BTBR mice. • S100A9 was overexpressed in the hippocampal microglia of BTBR mice. • S100A9 inhibition attenuated social dysfunction in BTBR mice. • S100A9 inhibition ameliorated neuroinflammation and reactive microglial three-dimensional structure. • S100A9 inhibition promoted myelination and reduced the c-Fos+ cells in the CA3 of BTBR mice. • Promyelinating clemastine improved autism-relevant behaviors in BTBR mice.

Source: Pharmacological Research

DOI: 10.1016/j.phrs.2024.107568