Cortical development dynamics across autism spectrum disorder mouse models.

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with over 100 known causal genes.
• Phenotypic convergence across diverse genetic models suggests shared underlying neurobiological mechanisms in ASD.

Purpose of the Study:

• To investigate common neurobiological processes in ASD by profiling multiple monogenic mouse models.
• To characterize developmental, cellular, and molecular dynamics across different ASD models, sexes, and brain regions.

Main Methods:

• Single-nucleus multi-omic sequencing of 251 samples from 11 monogenic ASD mouse models.
• Analysis across three developmental stages, both sexes, and two brain regions.
• Electrophysiological recordings to assess neuronal function.

Main Results:

• ASD-linked mutations converged on transient perturbations of the radial glial cell lineage, indicating developmental delays.
• Significant transcriptional differences were observed in neurons, with downregulation of synaptic and ion channel genes.
• Molecular convergence across models was stage-specific, becoming less pronounced over time.
• Sex-specific gene expression alterations were noted, with females often showing larger effect sizes.

Conclusions:

• Diverse ASD-associated mutations impinge on common, stage-specific neurodevelopmental processes.
• Findings reveal dynamic, transient cellular and molecular changes in ASD pathogenesis.
• The study provides a comprehensive view of ASD pathophysiology across multiple models and developmental time points.