Spatial and single-cell transcriptomics reveals senescence-associated changes in MIA-induced ASD male mouse brain

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, and maternal immune activation (MIA) is highly implicated in neuropathology and ASD-like phenotypes in offspring. However, the underlying regulatory mechanisms of ASD are multifactorial and remain largely unknown in MIA offspring. Here, we performed spatial transcriptome and single-nucleus RNA sequencing (snRNA-seq) analysis in MIA offspring brain to explore the neurobiological features of ASD. We obtained MIA-induced genes and pathways across multiple key brain regions. We found that senescence-associated APP-CD74 pathway, IGFBP7, and CDKN1A may act as the key pathogenic factors for ASD development. Our further analysis identified broad senescence-associated secretory phenotype (SASP) signature of MIA-induced ASD brain that are regulated in a cell-type specific manner. Moreover, we validated that pharmacological inhibition of IGFBP7 and CDKN1A effectively prevents ASD-like behaviors in MIA offspring. Collectively, our data reveal a senescence-associated regulatory mechanism for ASD, and provide potential intervention strategy for the treatment of ASD.