DNMT1 IN PV INTERNEURONS SUSTAINS CORTICAL STABILITY VIA OLIGODENDROCYTE REMODELING AND PERINEURONAL NET INTEGRITY

Parvalbumin-positive (PV) interneurons are critical regulators of cortical network stability. Their dysfunction has been implicated in neuropsychiatric disorders where DNA methyltransferase 1 (DNMT1) is often found dysregulated. Although DNMT1 has been shown to modulate inhibitory circuit function, the full scope of its cell-autonomous and non-cell-autonomous effects remains unclear. Using conditional PV-specific Dnmt1 knockout mice, we combined in vivo Neuropixels recordings, single-nucleus RNA sequencing, histological analyses, and behavioral assays to assess how DNMT1 loss in PV interneurons affects cortical circuits. In vivo electrophysiology revealed that DNMT1 loss increased spontaneous PV firing rates but paradoxically reduced their inhibitory efficacy on network activity. Sensory-evoked responses were weaker, temporally delayed, and less precise across cortical layers, while visually evoked gamma oscillations were severely impaired. These physiological alterations were accompanied by depression- and anxiety-like behaviors, including reduced home-cage activity, impaired nest building, decreased voluntary wheel running, and increased latency in novelty-suppressed feeding tests. Single-nucleus RNA-seq revealed extensive non-cell-autonomous transcriptional remodeling in oligodendrocytes, with downregulation of genes involved in extracellular matrix organization and perineuronal net (PNN) formation. Cell-cell communication analysis identified disrupted PV–oligodendrocyte coupling through reduced NRXN–NLGN, TNR–integrin, and NRG1–ERBB4 signaling which are critical for PNN stability. Histological validation confirmed a significant reduction of PNNs around PV interneurons in knockout mice. These findings demonstrate that DNMT1 maintains cortical network stability through coordinated regulation of PV interneuron function, glial transcriptional states, and extracellular matrix integrity, establishing an epigenetic mechanism linking inhibitory circuit dysfunction to network desynchronization and psychiatrically relevant behavioral phenotypes.