Hannah Kapell, Luca Fazio, Julia Dyckow, Sophia Schwarz, Andrés Cruz-Herranz, Christina Mayer, Joaquin Campos, Elisa D Este, Wiebke Möbius, Christian Cordano, Anne-Katrin Pröbstel, Marjan Gharagozloo, Amel Zulji, Venu Narayanan Naik, Anna-Katharina Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K Sonner, Jung H Sin, Paul Disse, Nicole Rychlik, Khalida Sabeur, Manideep Chavali, Rajneesh Srivastava, Matthias Heidenreich, Kathryn C Fitzgerald, Guiscard Seebohm, Christine Stadelmann, Bernhard Hemmer, Michael Platten, Thomas J Jentsch, Maren Engelhardt, Thomas Budde, Klaus-Armin Nave, Peter A Calabresi, Manuel A Friese, Ari J Green, Claudio Acuna, David H Rowitch , Sven G Meuth, Lucas Schirmer.
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.
J Clin Invest. 2023 Jan 31:e164223
Link to Pubmed