Sex-biased single-cell genetic landscape in mice with autism spectrum disorder

Autistic spectrum disorder (ASD) is a male-biased, heterogeneous neurodevelopmental disorder that affects approximately 1%-2% of the population. Prenatal exposure to valproic acid (VPA) is a recognized risk factor for ASD, but the cellular and molecular basis of VPA-induced ASD at the single-cell resolution is unclear. Here, we aim to compare the cellular and molecular differences in the hippocampus between male and female prenatal mice with ASD at the single-cell transcriptomic level. The transcriptomes of more than 45,000 cells are assigned to 12 major cell types, including neurons, glial cells, vascular cells, and immune cells. Cell type-specific genes with altered expression after prenatal VPA exposure are analyzed, and the largest number of differentially expressed genes (DEGs) are found in neurons, choroid plexus epithelial cells, and microglia. In microglia, several pathways related to inflammation are found in both males and females, including the tumor necrosis factor (TNF), nuclear factor kappa B (NF-κB), toll-like receptor (TLR), and mitogen-activated protein kinase (MAPK) signaling pathways, which are important for the induction of autistic-like behavior. Additionally, we note that several X-linked genes, including Bex1, Bex3, and Gria3, were among the male-specific DEGs of neurons. This pioneering study describes the landscape of the transcriptome in the hippocampus of autistic mice. The elucidation of sexual differences could provide innovative strategies for the prevention and treatment of ASD.