Perineuronal oligodendrocyte and myelin renewal are epigenetically silenced contributing 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 well-identified in SCZ patients. Cognitive processing highly relies on the myelination in the adult brain. However, whether and how OLs and myelin dynamics contribute to disease pathology remains unexplored. Here, we characterized a preferential loss of perineuronal OLs in both the dizocilpine (MK801)-induced mouse model and postmortem SCZ brain tissue. The extent of myelination was decreased in the medial prefrontal cortex (mPFC) of MK801 mice. Strikingly, spontaneous myelin renewal was suppressed due to a global deficiency in H3 lysine 4 trimethylation (H3K4me3) in OLs. Conditional knockout of Setd1a, the specific H3K4 methyltransferase in oligodendroglia precursor cells (OPCs), impaired myelination. Notably, pharmacologically counteracting H3K4me3 deficiency repaired OLs and myelin deficits and promoted cognitive recovery in MK801 mice. Taken together, these results demonstrate H3K4me3 status as a new potential target enhancing myelin repair to alleviate SCZ-related cognitive impairment.