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

Abstract

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.

Keywords: GABAergic; PGC-1α; cerebral cortex; development; gene expression; interneuron; maturation; metabolism; mitochondria; parvalbumin.