Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports their function

Parvalbumin‐positive (PV + ) fast‐spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV + interneurons imposes high‐energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single‐cell transcriptomic data for the mouse cortex, we identified a metabolism‐associated gene with highly restricted expression to PV + interneurons: Cox6a2 , which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV + interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV + interneurons, underscored by a decrease in the ATP‐to‐ADP ratio in Cox6a2 − / − PV + interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV + interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2 , we found a potential association of the mutations with mental/neurological abnormalities. Synopsis Whether brain neurons firing at high frequency depend on distinct metabolic machineries to satisfy their increased energy demands remains unclear. Here, combined genetic, functional and behavioural analyses reveal a selective role for the oxidative phosphorylation in stress protection of interneuron by safeguarding their energy supply. Mitochondrial complex IV subunit isoform Cox6a2 is enriched in parvalbumin‐positive (PV + ) interneurons in the adult rodent, rhesus monkey, and human brain. PV + interneuron‐specific Cox6a2 ablation decreases cellular ATP levels and increases oxidative stress in mice. Cox6a2 loss impairs transcriptional and morphological maturation during postnatal stages. Adult Cox6a2‐depleted PV + interneurons are hyperexcitable and defective in repetitive firing. Cox6a2 depletion results in hyperactivity in vivo . Graphical Abstract High‐frequency‐firing brain interneurons rely on cell type‐specific energy metabolism to avoid oxidative stress.