SCN2A-linked myelination deficits and synaptic plasticity alterations drive auditory processing disorders in ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by complex sensory processing deficits. A key unresolved question is how alterations in neural connectivity and communication translate into the behavioral manifestations seen in ASD. Here, we investigate how oligodendrocyte dysfunction alters myelin plasticity and neuronal activity, leading to auditory processing disorder associated with ASD. We focus on the gene, an ASD-risk factor, to understand its role in myelination and neural processing within the auditory nervous system. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes in conditional knockout mice, highlighting the cellular consequences engendered by deletion in oligodendrocytes. The results reveal a nuanced interplay between oligodendrocytes and axons, where deletion causes alterations in the intricate process of myelination. This disruption instigates changes in axonal properties, presynaptic excitability, and synaptic plasticity at the single cell level. Furthermore, oligodendrocyte-specific deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity. Our findings reveal a novel pathway linking myelin deficits to synaptic activity and sensory abnormalities in ASD.