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Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination

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Item Type:Article
Title:Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
Creators Name:Kapell, H., Fazio, L., Dyckow, J., Schwarz, S., Cruz-Herranz, A., Campos, J., Mayer, C., D Este, E., Möbius, W., Cordano, C., Pröbstel, A.K., Gharagozloo, M., Zulji, A., Narayanan Naik, V., Delank, A.K., Cerina, M., Müntefering, T., Lerma-Martin, C., Sonner, J.K., Sin, J.H., Disse, P., Rychlik, N., Sabeur, K., Chavali, M., Srivastava, R., Heidenreich, M., Fitzgerald, K.C., Seebohm, G., Stadelmann, C., Hemmer, B., Platten, M., Jentsch, T.J., Engelhardt, M., Budde, T., Nave, K.A., Calabresi, P.A., Friese, M.A., Green, A.J., Acuna, C., Rowitch, D.H., Meuth, S.G. and Schirmer, L.
Abstract:Multiple sclerosis (MS) is a progressive inflammatory-demyelinating disease of the central nervous system. 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 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 mice. In summary, our findings indicate that neuron-oligodendrocyte compensatory interactions promote resilience through Kv7 and Kir4.1 channels and suggest pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.
Keywords:Inflammation, Neuroscience, Animals, Mice
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation
Volume:133
Number:7
Page Range:e164223
Date:3 April 2023
Official Publication:https://doi.org/10.1172/jci164223
PubMed:View item in PubMed

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