Moissidis Monika, Abbasova Leyla, Selten Martijn, Alis Rafael, Bernard Clémence, Domínguez-Canterla Yaiza, Oozeer Fazal, Qin Shenyue, Kelly Audrey, Mòdol Laura, Vasistha Navneet A, Jones Benjamin, Dhami Pawan, Khodosevich Konstantin, Hamid Fursham, Lavender Paul, Flames Nuria, Marín Oscar
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.
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.
Cell. 2025 Jul 8. doi: 10.1016/j.cell.2025.06.029.
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.
皮层神经元在胚胎发育期间就已确定，但通常在出生后发育的相对晚期才获得其成熟特性。这种终末分化的延迟在快速放电的表达小白蛋白（PV）的中间神经元中尤为突出，这些中间神经元在调节大脑皮层功能中发挥着关键作用。我们发现，PV中间神经元的成熟由神经元活动触发，并由转录辅因子过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）介导。PGC-1α在发育过程中的缺失会阻止PV中间神经元获得独特的结构、电生理、突触和代谢特征，并破坏它们分化为不同亚型的过程。PGC-1α通过一个包括ERRγ和Mef2c转录因子的转录复合物直接控制基因表达，从而作为PV中间神经元分化的主要调节因子发挥作用。我们的研究结果揭示了一个分子开关，它将神经活动转化为特定的转录程序，促进PV中间神经元在适当的发育阶段成熟。
