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 ofPV(+)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 toPV(+)interneurons:Cox6a2, which codes for an isoform of a cytochromecoxidase subunit.Cox6a2deletion in mice disrupts perineuronal nets and enhances oxidative stress inPV(+)interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role ofCOX6A2 in energy balance ofPV(+)interneurons, underscored by a decrease in the ATP-to-ADP ratio inCox6a2(-/-)PV(+)interneurons. Energy disbalance and aberrant maturation likely hinder the integration ofPV(+)interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations inCOX6A2, we found a potential association of the mutations with mental/neurological abnormalities.