A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons.

1. Cell. 2025 Oct 2;188(20):5555-5575.e26. doi: 10.1016/j.cell.2025.06.029. Epub 2025 Jul 15. A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons. Moissidis M(1), Abbasova L(1), Selten M(1), Alis R(2), Bernard C(1), Domínguez-Canterla Y(2), Oozeer F(1), Qin S(1), Kelly A(3), Mòdol L(1), Vasistha NA(4), Jones B(5), Dhami P(5), Khodosevich K(4), Hamid F(1), Lavender P(3), Flames N(2), Marín O(6). Author information: (1)Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK; Medical Research Council Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, UK. (2)Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia IBV-CSIC, Valencia 46012, Spain; Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), Associated Unit to the Instituto de Biomedicina de Valencia (IBV), Valencia 46012, Spain. (3)Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King's College London, London SE1 9RT, UK; King's Centre for Lung Health, King's College London, London SE1 9RT, UK. (4)Biotech Research and Innovation Center (BRIC), Copenhagen Biocenter, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. (5)Genomics Research Platform and Single Cell Laboratory, Guy's Hospital, London SE1 9RT, UK. (6)Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK; Medical Research Council Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, UK. Electronic address: oscar.marin@kcl.ac.uk. Cortical neurons are specified during embryonic development but often acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the function of the cerebral cortex. We found that the maturation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α). Developmental loss of PGC-1α prevents PV+ interneurons from acquiring unique structural, electrophysiological, synaptic, and metabolic features and disrupts their diversification into distinct subtypes. PGC-1α functions as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERRγ and Mef2c transcription factors. Our results uncover a molecular switch that translates neural activity into a specific transcriptional program, promoting the maturation of PV+ interneurons at the appropriate developmental stage. Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.cell.2025.06.029 PMID: 40669459 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests The authors declare no competing financial interests.