Single‐Cell Integration of Mouse Models of Autism Reveals Conserved Transcriptomic Signatures of Excitatory‐Inhibitory Imbalance and Glial Dysfunction

ABSTRACT The etiological heterogeneity of autism spectrum disorder (ASD) complicates identifying core molecular mechanisms. We systematically integrated scRNA‐seq data from 11 diverse genetic and environmental mouse ( Mus musculus ) models, encompassing > 300,000 cells across multiple brain regions and developmental stages. Using advanced computational harmonization (RPCA), we identified robust convergent transcriptomic signatures that transcend model‐specific variability. Our findings reveal widespread alterations in neuronal communication pathways, specifically increased excitatory‐inhibitory signaling involving PTN, SLIT, and PTPR pathways. Furthermore, cell–cell communication analysis via NicheNet prioritized ligand‐receptor pairs associated with altered circuit excitability, offering a predictive blueprint of dysregulated intercellular crosstalk. Crucially, we identified significant glial involvement characterized by astrocyte function inhibition, marked by Aqp4 and Kcnj10 downregulation related to impaired water/potassium homeostasis and mature oligodendrocyte metabolic dysregulation through Olig family upregulation and enhanced oxidative phosphorylation. Differentially expressed genes (DEGs) significantly overlapped with SFARI‐listed high‐confidence risk genes, particularly within excitatory neuronal subtypes. Comparison with human postmortem single‐nucleus data from the prefrontal and parietal cortices demonstrated conserved signatures related to impaired synaptic protein synthesis (GRIN2B, CAMK2A) and oligodendrocyte‐mediated neurodevelopmental deficits (NRXN, DLGAP). This study confirms that E/I imbalance and glial dysfunction are universal cellular pathologies in ASD, providing a robust, large‐scale reference for identifying novel therapeutic targets with single‐cell resolution.