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

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.