Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.
Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.
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DOI：
10.1172/jci164223
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发表时间：
2023-04-03
影响因子：
15.9
通讯作者：
Schirmer, Lucas
中科院分区：
文献类型：
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作者：
Kapell, Hannah;Fazio, Luca;Dyckow, Julia;Schwarz, Sophia;Cruz-Herranz, Andres;Mayer, Christina;Campos, Joaquin;D'Este, Elisa;Moebius, Wiebke;Cordano, Christian;Probstel, Anne-Katrin;Gharagozloo, Marjan;Zulji, Amel;Naik, Venu Narayanan;Delank, Anna;Cerina, Manuela;Muentefering, Thomas;Lerma-Martin, Celia;Sonner, Jana K.;Sin, Jung Hyung;Disse, Paul;Rychlik, Nicole;Sabeur, Khalida;Chavali, Manideep;Srivastava, Rajneesh;Heidenreich, Matthias;Fitzgerald, Kathryn C.;Seebohm, Guiscard;Stadelmann, Christine;Hemmer, Bernhard;Platten, Michael;Jentsch, Thomas J.;Engelhardt, Maren;Budde, Thomas;Nave, Klaus-Armin;Calabresi, Peter A.;Friese, Manuel A.;Green, Ari J.;Acuna, Claudio;Rowitch, David H.;Meuth, Seven G.;Schirmer, Lucas
多发性硬化症(MS)是一种进行性中枢神经系统炎症性脱髓鞘疾病。越来越多的证据表明，随着时间的推移，MS中脆弱的神经元表现出致命的代谢衰竭，这种现象被认为是由慢性过度兴奋引起的。轴突KV7(外向整流钾通道)和少突胶质细胞Kir4.1钾通道(内向整流钾通道)在调节Ranvier结节及其周围神经元兴奋性方面起着重要作用。在这里，我们研究了神经元KV7和少突胶质细胞Kir4.1通道之间的空间和功能关系，并评估了生理性和炎症性脱髓鞘条件下皮质和视网膜投射神经元的转录和功能特征。我们发现，在MS和实验性自身免疫性脑脊髓炎(EAE)中，这两个通道都变得失调，其中Kir4.1通道在炎性脱髓鞘过程中慢性下调，KV7通道亚单位一过性上调。此外，我们观察到，药物KV7通道的开放降低了人和EAE神经元的神经元过度兴奋性，改善了临床EAE体征，并挽救了少突胶质细胞Kir4.1缺陷(OL Kir4.1缺陷)小鼠的神经元病理。综上所述，我们的研究结果表明，神经元-OL的代偿性相互作用通过KV7和Kir4.1通道促进了韧性，并确定了药理学上激活结节KV7通道是一种对抗炎性脱髓鞘的神经保护策略。
Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte–Kir4.1–deficient (OL-Kir4.1–deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.