DNMT1 function in cortical PV interneurons modulates cortical network activity, mood disorder‑related behavior, and perineuronal nets

Abstract Parvalbuminergic (PV) interneurons are central to cortical network stability and psychiatric vulnerability. Here, we identify DNA methyltransferase 1 (DNMT1) as a key epigenetic regulator linking PV interneuron function to glial and extracellular matrix remodeling. Conditional PV-specific Dnmt1 deletion, combined with single-nucleus RNA-seq (snRNA-seq), snATAC-seq, in vivo electrophysiology, histology, and behavioral analyses, revealed that DNMT1 loss increases PV spiking but reduces inhibitory efficacy, driving network desynchronization and depression- and anxiety-like behavior in mice. These physiological changes were accompanied by non-cell-autonomous transcriptional and chromatin alterations, affecting perineuronal net (PNN) organization and neuron-glia communication. Cell-cell communication analyses predicted reorganized perisomatic signaling, and compartmental modeling of oligodendrocyte lineage dynamics further revealed impaired formation of PNN-supporting perineuronal oligodendrocytes, consistent with a tissue-level reduction in PNN integrity. Together, our findings demonstrate that DNMT1 maintains inhibitory circuit stability through PV interneuron function, secondarily shaping glial states and extracellular scaffolds to support cortical network synchronization and affective behavior.