Epigenetic silencing of perineuronal oligodendrocyte generation and myelin renewal contributes to cognitive deficits in a murine model of schizophrenia
Cognitive deficits are core symptoms of schizophrenia (SCZ) and major contributors to disability. Beyond gray matter loss, significant oligodendrocytes (OLs) and myelin pathologies have been documented in SCZ patients. Cognitive processing critically relies on the myelination in the adult brain. However, whether and how OL and myelin dynamics contribute to disease pathology remains unexplored. Here, we characterized a preferential loss of perineuronal OLs in both dizocilpine (MK801)-induced mouse models and postmortem SCZ brain tissues. Myelination was decreased in the medial prefrontal cortex (mPFC) of MK801 treated mice. Strikingly, spontaneous myelin renewal was suppressed due to a global deficiency in H3 lysine 4 trimethylation (H3K4me3) in oligodendroglia precursor cells (OPCs). Conditional knockout of Setd1a in OPCs, which encodes a key H3K4 methyltransferase, impaired myelination. Notably, pharmacologically counteracting H3K4me3 deficiency reversed OLs and myelin deficits and promoted cognitive recovery in MK801 mice. Taken together, these results establish H3K4me3 status as a potential new target for enhancing myelin repair to alleviate SCZ-related cognitive impairment.