Developmental dynamics of the cortical cellular and molecular landscapes in autism spectrum disorder models

Recent research has identified over 100 causal genes in autism spectrum disorder (ASD), raising the question of how mutations in genes with diverse functions result in similar clinical presentations. Here, we profiled 251 samples from eleven monogenic ASD mouse models using single-nucleus multi-omic sequencing across three developmental stages, both sexes, and two brain regions. We discovered that, despite wide genetic heterogeneity, ASD-linked mutations converged on perturbations of the radial glial cell lineage. This converging alteration primarily reflects a transient developmental delay rather than a lasting lineage misspecification and resolves by postnatal stages. Molecularly, the largest transcriptional differences emerged in neurons at early postnatal stages. These changes included downregulation of synaptic and ion channel-related genes, consistent with homeostatic adaptation or delayed maturation. Network analysis indicated that molecular convergence is strong across models within each developmental stage, suggesting that diverse ASD mutations impinge on common, stage-specific processes. Convergence becomes less pronounced by postnatal day 14, highlighting the dynamic nature of ASD-associated changes. Cross-genotype heterogeneity is superimposed on stage-specific effects. Electrophysiology corroborated this pattern: mutants generally showed altered neuronal excitability and synaptic properties with model-specific nuances. Our study also highlighted sex-specific gene expression alterations, with females often displaying larger effect sizes than males. Altogether, our findings provide a comprehensive view of the developmental cellular and molecular dynamics across ASD models.