Scn2a-linked myelination deficits and synaptic plasticity alterations drive auditory processing disorders in an ASD mouse model

Han-Gyu Bae, Wan-Chen Wu, Kaila Nip, Elizabeth Gould and Jun Hee Kim ()
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Han-Gyu Bae: University of Michigan
Wan-Chen Wu: University of Michigan
Kaila Nip: University of Texas Health Science Center
Elizabeth Gould: University of Texas Health Science Center
Jun Hee Kim: University of Michigan

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by complex sensory processing deficits, which continue to elude comprehensive mechanistic understanding. 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 SCN2A gene, an ASD-risk factor, to understand its role in myelination and neural processing within the auditory nervous system. Transcriptional profiling suggests alterations in the expression of myelin-associated genes in Scn2a conditional knockout mice, highlighting the cellular consequences engendered by Scn2a deletion in oligodendrocytes. The results reveal a nuanced interplay between oligodendrocytes and axons, where Scn2a 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 Scn2a deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity. Our findings reveal a pathway linking myelin deficits to synaptic activity and sensory abnormalities in ASD.

Date: 2025
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DOI: 10.1038/s41467-025-62494-3

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