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.

中文翻译：

---

复杂的 IV 亚基亚型 COX6A2 可保护快速放电的中间神经元免受氧化应激并支持其功能。


小白蛋白阳性 (PV ⁺ ) 快速放电中间神经元对于控制主要神经元群的放电活动至关重要，从而调节认知过程。 PV ⁺中间神经元的高放电频率活动对其新陈代谢提出了高能量需求，而这些能量必须由独特的能量产生机制提供。通过探索小鼠皮质的单细胞转录组数据，我们发现了一种对 PV ⁺中间神经元表达高度受限的代谢相关基因： Cox6a2 ，它编码细胞色素c氧化酶亚基的异构体。小鼠Cox6a2缺失会破坏神经周围网络并增强 PV ⁺中间神经元的氧化应激，进而损害其形态和功能特性的成熟。这种巨大的影响可能是由于 COX6A2 在 PV ⁺中间神经元能量平衡中的重要作用， Cox6a2 ^{- / -} PV ⁺中间神经元中 ATP 与 ADP 比率的下降强调了这一点。能量失衡和异常成熟可能会阻碍 PV ⁺中间神经元整合到皮质神经元回路中，从而导致小鼠行为改变。此外，在一名携带​​ COX6A2突变的人类患者中，我们发现这些突变与精神/神经异常存在潜在关联。