Developmental prefrontal myelination shapes inhibitory interneuron function and adult social behavior

Abstract

Early-life adversity and abnormal myelination are implicated in psychiatric disorders, but how developmental myelination influences adult social cognition remains unclear. Here, we tested whether disrupting developmental myelination in the medial prefrontal cortex (mPFC) impairs adult social behavior. Using complementary genetic strategies in male mice, we suppressed Myelin Regulatory Factor (Myrf)-dependent myelination locally in the juvenile mPFC or broadly in oligodendrocyte-lineage cells. Both approaches selectively impaired adult social novelty preference while sparing sociability, locomotion, and affective behaviors. Focal prefrontal dysmyelination also reduced social dominance. Spatial transcriptomics revealed coupling between myelin-related genes and parvalbumin (PV) interneuron markers in the healthy mPFC, which was disrupted by developmental hypomyelination. Consistent with this transcriptional alteration, PV interneurons showed reduced high-frequency firing despite preserved intrinsic excitability. In the human prefrontal cortex, MBP–PV expression was correlated in controls but not in individuals with schizophrenia. These findings indicate that developmental prefrontal myelination contributes to PV interneuron maturation and suggest that disrupted oligodendrocyte–interneuron coordination may contribute to impaired social recognition.