DNMT1 function in cortical PV interneurons modulates cortical network activity, mood disorder‑related behavior, and perineuronal nets
Communications Biology, vol. 9
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.
Authors 19
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Gerion Nabbefeld Aachen Department for Molecular and Systemic Neurophysiology Institute for Biology II
Affiliation as printed
Department for Molecular and Systemic Neurophysiology, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Severin Graff Aachen
Forschungszentrum Jülich · RWTH Aachen University
Affiliation as printed
Institute of Biological Information Processing (IBI-3) Bioelectronics, Forschungszentrum Jülich, Jülich, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Computational Biomedicine and Disease Modeling, RWTH Aachen University Hospital, Aachen, Germany
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Affiliation as printed
Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Björn M. Kampa Aachen Department for Molecular and Systemic Neurophysiology Institute for Biology II
Affiliation as printed
Department for Molecular and Systemic Neurophysiology, Institute for Biology II, RWTH Aachen University, Aachen, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Neurology, Jena University Hospital, Jena, Germany
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Simon Musall Aachen
Forschungszentrum Jülich · RWTH Aachen University
Affiliation as printed
Institute of Biological Information Processing (IBI-3) Bioelectronics, Forschungszentrum Jülich, Jülich, Germany
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany
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Geraldine Zimmer‐Bensch corresponding Aachen Department for Neuroepigenetics Institute for Biology II
Affiliation as printed
Department for Neuroepigenetics, Institute for Biology II, RWTH Aachen University, Aachen, Germany. zimmer@bio2.rwth-aachen.de
Research Training Group RTG2416 "MultiSenses - MultiScales", RWTH Aachen University, Aachen, Germany. zimmer@bio2.rwth-aachen.de