A postnatal molecular switch drives the activity-dependent maturation of parvalbumin interneurons [scRNA-seq]

Cortical neurons are specified during embryonic development but often only 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 activity of the cerebral cortex. We found that the terminal differentiation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1a). Developmental loss of PGC-1a prevents PV+ interneurons from acquiring their unique structural, electrophysiological, synaptic, and metabolic features and disrupts PV+ interneuron subtype specification. PGC-1a exerts its function as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERRg and Mef2c. Our results uncover a molecular switch that translates neural activity into transcriptional programs promoting the maturation of PV+ interneurons at the appropriate developmental stage. Overall design: PV+ and SST+ interneurons from Lhx6-Cre;Ppargc1a+/+ (control) and Lhx6-Cre;Ppargc1aF/F (mutant) animals were isolated using FACS, thanks to the expression of tdT after viral infection. These sorted cells were then subjected to single-cell RNA sequencing.