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

Berta Sanz-Morello, Ulrich Pfisterer, Nikolaj Winther Hansen, Samuel Demharter, Ashish Thakur, Katsunori Fujii, Sergey A. Levitskii, Alexia Montalant, Irina Korshunova, Pradeep P.A. Mammen, Piotr Kamenski, Satoru Noguchi, Blanca Irene Aldana, Karin Sørig Hougaard, Jean François Perrier, Konstantin Khodosevich

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalEMBO Journal
DOIs
StateAccepted/In press - 2020

Keywords

  • energy production
  • high-frequency firing
  • interneurons
  • oxidative stress
  • parvalbumin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Sanz-Morello, B., Pfisterer, U., Winther Hansen, N., Demharter, S., Thakur, A., Fujii, K., Levitskii, S. A., Montalant, A., Korshunova, I., Mammen, P. P. A., Kamenski, P., Noguchi, S., Aldana, B. I., Hougaard, K. S., Perrier, J. F., & Khodosevich, K. (Accepted/In press). Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function. EMBO Journal. https://doi.org/10.15252/embj.2020105759