Myelin dysfunction in autism spectrum disorder: insights into core symptoms and mechanisms of brain development

Abstract Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with multifactorial etiologies. Although much research has historically focused on neurons, growing evidence indicates that multiple cell types within the central nervous system (CNS), particularly glial cells, also play critical roles. Importantly, glial cells express most of the high-confidence ASD (hc-ASD) genes, and mutations in these genes are strongly associated with an increased risk of ASD. These cells also play a crucial role in the development, refinement and maturation of circuits. This review highlights the central role of oligodendrocytes (OLs) and myelin in ASD pathophysiology. Individuals with ASD frequently exhibit impairments in white matter development and integrity, particularly in brain regions associated with sociability, stereotyped behaviors, and decision-making. These findings are supported by advanced CNS imaging and postmortem analyses, including structural, proteomic, and transcriptomic studies. Rodent models that replicate core ASD symptoms, such as social disinterest and restricted/repetitive behaviors, demonstrate that aberrant myelination profoundly affects these behavioral traits. Moreover, perturbations in oligodendroglial development directly alter CNS architecture, leading to neuronal morphological abnormalities and disruptions in excitation/inhibition balance. The correlation between OL dysfunction, altered brain architecture, and ASD symptoms underscores the importance of studying OLs in the context of ASD. A comprehensive understanding of the interplay between OL function and ASD pathophysiology could inform the development of targeted therapeutic strategies aimed at restoring white matter integrity and improving functional outcomes.