Developmental prefrontal myelination shapes inhibitory interneuron function and adult social behavior

Early-life adversity and abnormal myelination have been linked to psychiatric disorders, yet the exact impact of developmental myelination on adult social cognition remains uncertain. This study explored whether interfering with myelination during brain development in the medial prefrontal cortex (mPFC) would affect adult social behavior.

Employing genetic strategies, the researchers inhibited Myelin Regulatory Factor (Myrf)-dependent myelination in either a local area of the juvenile mPFC or throughout oligodendrocyte-lineage cells. Both interventions selectively impaired adult social novelty preference without affecting sociability, locomotion, or affective behaviors.

Focal disruption of prefrontal myelination also reduced social dominance. Spatial transcriptomics showed a link between myelin-related genes and parvalbumin (PV) interneuron markers in the normal mPFC, which was disrupted by developmental hypomyelination. The altered transcription resulted in reduced high-frequency firing of PV interneurons, despite their intrinsic excitability remaining unchanged.

In human subjects, an association between MBP-PV expression in the prefrontal cortex was observed in controls but not in individuals with schizophrenia. These results suggest that developmental myelination in the prefrontal cortex contributes to PV interneuron maturation and imply that disrupted coordination between oligodendrocytes and interneurons may lead to impaired social recognition.