14/07/25
The functioning of our cerebral cortex relies upon a vast diversity of neurons to function properly. This includes fast-spiking parvalbumin-expressing (PV+) interneurons, who are critical regulators of network activity and enable cognitive processes. Although these cells are specified during embryonic development, they only acquire their mature properties postnatally, much later compared to other neuronal cell types. An exciting new study from Monika Moissidis and colleagues in the Marín lab, published in Cell, shows that the maturation of PV+ interneurons depends on neuronal activity, and in particular on their integration within cortical networks. This activates a molecular mechanism that controls the terminal differentiation of PV+ interneurons.
In their study, the team identified the transcriptional cofactor PGC-1α as a key regulator of PV+ interneuron maturation. PGC-1α expression in PV+ interneurons increases at postnatal ages and depends on neuronal activity, therefore linking activity to the terminal differentiation of these cells. More precisely, loss of PGC-1α disrupted the acquisition of neurochemical, electrophysiological, synaptic, and metabolic features specific to mature PV+ interneurons, while PGC-1α overexpression accelerated their maturation process. Single-cell RNA sequencing showed that PGC-1α controls the expression of a broad transcriptional programme, and does so by directly interacting at the regulatory regions of genes, acting in concert with the transcription factors ERRγ and Mef2c.
Moissidis et al.’s work identifies PGC-1α as a ‘molecular switch’ that translates neuronal activity into a gene expression programme which drives the maturation and diversification of PV+ interneurons. The team’s findings are an important step forward in understanding how cortical circuits develop and the mechanisms behind neurodevelopmental disorders, where PV+ interneuron function is impaired.
