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.
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BibTeX
@article{linde2026dnmt1,
title = {{DNMT1 function in cortical PV interneurons modulates cortical network activity, mood disorder‑related behavior, and perineuronal nets}},
author = {Jenice Linde and Can Bora Yildiz and Katharina Vöhringer and Gerion Nabbefeld and Severin Graff and Daniel Pensold and Julia Reichard and Marie Hermanns and Laura Koch and Magdalena Sophie Müller and Ayushi Tanwar and Christoph Weber-Hamacher and Ivan G. Costa Filho and Thomas Stiehl and Marc Spehr and Björn Kampa and Anja Urbach and Simon Musall and Geraldine Zimmer-Bensch},
journal = {Communications Biology},
year = {2026},
month = oct,
doi = {10.1038/s42003-026-11079-x},
url = {https://www.nature.com/articles/s42003-026-11079-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - DNMT1 function in cortical PV interneurons modulates cortical network activity, mood disorder‑related behavior, and perineuronal nets
AU - Jenice Linde
AU - Can Bora Yildiz
AU - Katharina Vöhringer
AU - Gerion Nabbefeld
AU - Severin Graff
AU - Daniel Pensold
AU - Julia Reichard
AU - Marie Hermanns
AU - Laura Koch
AU - Magdalena Sophie Müller
AU - Ayushi Tanwar
AU - Christoph Weber-Hamacher
AU - Ivan G. Costa Filho
AU - Thomas Stiehl
AU - Marc Spehr
AU - Björn Kampa
AU - Anja Urbach
AU - Simon Musall
AU - Geraldine Zimmer-Bensch
PY - 2026
DA - 2026/10/08
JO - Communications Biology
DO - 10.1038/s42003-026-11079-x
UR - https://www.nature.com/articles/s42003-026-11079-x
AB - 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.
SN - 2399-3642
ER -