瑞士苏黎世大学Aiman S. Saab团队发现，少突胶质细胞-轴突代谢耦合由细胞外K⁺介导并维持轴突健康。该项研究成果于2024年1月24日在线发表在《自然—神经科学》杂志上。

为了确定少突胶质细胞（OL）如何检测轴突脉冲以及如何调节白质中轴突-OL的快速代谢耦合，研究人员揭示了小鼠视神经中依赖于活动的钙离子（Ca²⁺）和代谢通量。研究表明，轴突的快速轴突脉冲会触发Ca²⁺信号传导和OL中的糖酵解。OL通过增加细胞外钾（K⁺）浓度和激活Kir4.1通道来检测轴突活动，从而调节轴突的代谢物供应。Kir4.1的药物抑制和OL特异性失活都会减少活动诱导的轴突乳酸激增。

缺乏少突胶质细胞Kir4.1的小鼠表现出较低的静息乳酸水平和轴突葡萄糖代谢的改变。轴突能量代谢的这些早期缺陷与晚期轴突病变有关。这些研究结果表明，OL通过K⁺信号检测快速的轴突脉冲，使急性代谢耦合成为可能，并调整轴突-OL代谢单元以促进轴突健康。

研究人员表示，有髓鞘轴突的完整性依赖于OL的平衡支持。

附：英文原文

Title: Oligodendrocyte–axon metabolic coupling is mediated by extracellular K+ and maintains axonal health

Author: Looser, Zoe J., Faik, Zainab, Ravotto, Luca, Zanker, Henri S., Jung, Ramona B., Werner, Hauke B., Ruhwedel, Torben, Mbius, Wiebke, Bergles, Dwight E., Barros, L. Felipe, Nave, Klaus-Armin, Weber, Bruno, Saab, Aiman S.

Issue&Volume: 2024-01-24

Abstract: The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon–OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca2+) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K+) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K+ signaling, making acute metabolic coupling possible and adjusting the axon–OL metabolic unit to promote axonal health.

DOI: 10.1038/s41593-023-01558-3

Source: https://www.nature.com/articles/s41593-023-01558-3