DNMT1 Coordinates PV Interneuron-Glia Coupling to Maintain Cortical Network Stability and Regulate Behavior
Parvalbumin (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-cell RNA-seq, in vivo electrophysiology, histology, and behavioral analyses revealed that loss of DNMT1 increases PV spiking activity but reduces inhibitory efficacy, leading to network desynchronization and depression- and anxiety-like behavior in mice. These physiological alterations were accompanied by broad, non-cell-autonomous transcriptional changes in astrocytes and oligodendroglial populations, prominently affecting pathways involved in perineuronal-net (PNN) organization and neuron-glia communication. Cell-cell interaction analyses revealed disrupted NRXN-NLGN, TNR-integrin, and semaphoring signaling, consistent with weakened perisomatic adhesion and PNN integrity. Together, our findings demonstrate that DNMT1 maintains inhibitory circuit stability through cell-autonomous regulation of PV interneuron function, which secondarily shapes glial transcriptional states and extracellular scaffolds to preserve cortical network synchronization and emotional behavior.