DNMT1 Coordinates PV Interneuron–Glia Coupling to Maintain Cortical Network Stability and Regulate Behavior
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract 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.
Authors 14
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Affiliation as printed
RWTH Aachen University, Division of Neuroepigenetics, Institute Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neuroepigenetics, Institute Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany
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Affiliation as printed
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 5074 Aachen, Germany
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Katharina Vöhringer Aachen Department for Neuroepigenetics Institute for Biology II Department of Neuroepigenetics
Affiliation as printed
Department for Neuroepigenetics , Institute for Biology II , RWTH Aachen University
Research Training Group RTG2416 " MultiSenses -MultiScales" , RWTH Aachen University
RWTH Aachen University, Department of Neuroepigenetics
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Affiliation as printed
RWTH Aachen University, Division of Neurophysiology, Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neurophysiology, Institute for Biology II, Worringerweg 3, 5207 Aachen, Germany
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Affiliation as printed
Institute of Biological Information Processing (IBI-3) Bioelectronics, Forschungszentrum Juelich, Germany;
Institute of Biological Information Processing (IBI-3) Bioelectronics, Forschungszentrum Juelich, Germany
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Affiliation as printed
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 5074 Aachen, Germany
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Affiliation as printed
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 5074 Aachen, Germany
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Affiliation as printed
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 5074 Aachen, Germany
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Affiliation as printed
Department of Chemosensation, Institute for Biology II, RWTH Aachen University; 52074 Aachen, Germany;
52074 Aachen, Germany
Department of Chemosensation, Institute for Biology II, RWTH Aachen University
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Marc Spehr Aachen
Affiliation as printed
RWTH Aachen University;
RWTH Aachen University
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Björn M. Kampa Aachen Department for Molecular and Systemic Neurophysiology Institute for Biology II
Affiliation as printed
RWTH Aachen University, Department for Molecular and Systemic Neurophysiology, Institute for Biology II;
RWTH Aachen University, Department for Molecular and Systemic Neurophysiology, Institute for Biology II
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Affiliation as printed
Department of Neurology, Jena University Hospital
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Affiliation as printed
Institute of Biological Information Processing (IBI-3) Bioelectronics, Forschungszentrum Juelich, Germany;
Institute of Biological Information Processing (IBI-3) Bioelectronics, Forschungszentrum Juelich, Germany
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Affiliation as printed
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 52074 Aachen, Germany;
RWTH Aachen University, Division of Neuroepigenetics, Institute for Biology II, Worringerweg 3, 5074 Aachen, Germany
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