Peiro-Moreno, C. | bioRxiv Science

bioRxiv2026

Oligodendroglial dysfunction drives parvalbumin interneuron hypomyelination, circuit dysfunction and social deficits in an ASD model

Altered social behaviour in autism spectrum disorders (ASDs) has been linked to disruptions in neural circuit development, with emerging evidence implicating abnormal myelination. Yet how myelin development is affected and how this impacts circuit function remain unclear. Here, using the cntnap2-/- mouse model of ASD, we show that oligodendrocyte precursor cell (OPC) differentiation is transiently impaired during early postnatal development, resulting in delayed myelination in the somatosensory cortex and corpus callosum, altered myelin lipid composition, and impaired sheath wrapping, accompanied by transient microgliosis and increased oligodendrocyte apoptosis. Transcriptomic analysis reveals upregulation of interferon and immune-related pathways alongside downregulation of GABAergic synaptic genes in oligodendrocytes. These alterations converge on disrupted GABAergic interneuron to OPC communication, leading to hypomyelination and impaired maturation of parvalbumin-positive (PV) interneurons through a non-cell-autonomous mechanism, with selective deficits in PV function, excitation/inhibition balance and gamma oscillations. Early treatment with the promyelinating agents clemastine or pranlukast restores OPC differentiation, myelination, and PV maturation, rescues circuit dysfunction, and ameliorates social deficits and behavioural inflexibility. Our findings establish that transient developmental failure in OPC differentiation drives PV interneuron hypomyelination, linking oligodendroglial dysfunction to circuit-level and behavioural alterations in ASD, and highlight early myelin-targeted interventions as a potential therapeutic strategy.

neuroscience↗

bioRxiv2025

Internalization of exogenous myelin by oligodendroglia promotes lineage progression

Oligodendrocytes, traditionally recognized for their role in central nervous system myelination, have emerged during the last decades as key participants maintaining brain homoeostasis in response to metabolic demands and stress. In addition, injury to myelin prompts a regenerative response that leads to the formation of new myelin sheaths. However, the signals regulating effective remyelination by oligodendrocytes are still not completely understood. Here, we report that oligodendrocytes can internalize exogenous myelin both in vitro and in vivo, which leads to an increase in their proliferation and differentiation when their functions are not compromised. RNA sequencing reveals that myelin debris alters oligodendrocyte transcriptional profile, suppressing immune-related pathways and de novo cholesterol and fatty acid biosynthesis, while inducing lipid droplet formation to store and process internalized myelin particles. As a result, progression of the oligodendroglial lineage is enhanced in primary cell cultures, as shown by increased viability, proliferation and differentiation. Oligodendrocytes also acquire a more differentiated phenotype, with larger cell areas, a more complex morphology and myelination of synthetic nanofibers. Stereotaxic injection of fluorescent myelin into mouse cortex shows internalization by microglia and, to a lesser extent, by oligodendroglia. Notably, in the zebrafish model, ventricular injections of myelin also increase the number of ventral oligodendrocytes in the spinal cord, further supporting that myelin can promote lineage progression. These findings challenge the classical view that myelin debris intrinsically inhibits oligodendrocyte proliferation, suggesting instead that oligodendrocytes can use myelin to support self-renewal and maturation, acting as a trophic factor in the absence of pathological cues. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/665370v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b15463org.highwire.dtl.DTLVardef@1b7090org.highwire.dtl.DTLVardef@17b148forg.highwire.dtl.DTLVardef@182d7d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗