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Myelination across the autism spectrum: therapeutic targeting of the oligodendrocyte lineage and myelination defects

Neuropsychopharmacology volume 51, pages 343–344 (2026)Cite this article

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Phenotypic heterogeneity in autism spectrum disorder (ASD) is perhaps the greatest of all the neuropsychiatric conditions. It spans from high-functioning individuals to profound neurodevelopmental disorders, and this is presumably a large contributor to our incomplete understanding of the etiology and pathophysiology of ASD. Recent studies using human induced pluripotent stem cells (hiPSCs) models of ASD are beginning to cut through this heterogeneity and are making headway towards discovering overarching etiological mechanisms.

If this etiological hypothesis is correct, its developmental timing will make it difficult to target therapeutically, because diagnoses are not made until several years after birth when neuronal density and specification is permanently established. In contrast, the OL lineage continues to proliferate throughout the lifespan, and myelination is a lifelong process that precedes and coincides with ASD diagnoses. Evidence for a role of OLs in ASD pathophysiology is accumulating, and suggests that modulation of myelination may be an important therapeutic target. Neuroimaging studies of syndromic ASD patients with single gene mutations consistently find delays in white matter development (e.g. ADNP, ADSL, ARID1B, BRAF, CREBBP, DLG4, EHMT1, FOXG1, GRIN1, MEF2C, POGZ, UBE3A, FMR1, TCF4). Single nucleus RNA sequencing of postmortem brain samples from idiopathic ASD cases identified enrichment of differentially expressed genes in OLs [4], and cellular deconvolution of bulk RNA sequencing predicted a reduction in the proportion of OLs in ASD [5]. Several pro-myelinating compounds are currently in clinical trials for multiple sclerosis and show promise for rescuing behavior in ASD mouse models [6]. To make progress on this potential therapeutic approach, better understanding of the prevalence and directionality of myelin defects across ASD is needed. We suggest that progress could be accelerated in future studies by limiting heterogeneity via focusing on genetically- and/or phenotypically-defined subsets of ASD patients.

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Fig. 1: ASD genetic risk converges on neural stem cell and oligodendrocyte precursor cells (OPC) proliferation and differentiation and leads to alterations in the proportion of cell types in the brain.

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Acknowledgements

This project was supported by the Lieber Institute for Brain Development, the National Institute of Mental Health (Grant No. R01MH110487 to BJM), and the Pitt-Hopkins Research Foundation and Penn Medicine Orphan Disease Center (Grant No. MDBR-24-002-PittHopkins to BJM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    Hyejung Won

  2. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    Brady J. Maher

  3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Brady J. Maher

  4. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Brady J. Maher

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  1. Hyejung Won
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  2. Brady J. Maher
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HW: Visualization, Writing—Review & Editing; BJM: Visualization, Writing—Original Draft, Writing—Review & Editing.

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Correspondence to Brady J. Maher.

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Won, H., Maher, B.J. Myelination across the autism spectrum: therapeutic targeting of the oligodendrocyte lineage and myelination defects. Neuropsychopharmacol. 51, 343–344 (2026). https://doi.org/10.1038/s41386-025-02209-w

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