Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
Hannah Kapell, et al.
Hannah Kapell, et al.
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Research Article Inflammation Neuroscience

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

Abstract

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.

Authors

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 Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K. Sonner, Jung Hyung 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

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Figure 3

Dysregulation of Kv7 subunits in cortical and retinal EAE tissues.

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Dysregulation of Kv7 subunits in cortical and retinal EAE tissues. (A) S...
(A) Spatial Kcnq3 expression (ISH) in the mouse cortex. (B) Overview plot visualizes different EAE groups including endpoints at 15, 30, and 60 dpi; note chronic EAE groups (endpoint at 60 dpi) were divided into 2 groups separating animals with or without clinical worsening (rebound). (C) Kcnq3 expression (ISH) in Syt1+ Rorb+ L4 mouse neurons at 14, 30, and 60 dpi in EAE (each, n = 4) and control (n = 3) mice; Kcnq3-KO mouse tissue showed a strong reduction in Kcnq3 expression (n = 4). (D) Density of Kv7.2+ nodes (framed by Caspr+ IR) based on IR in L4 cortical areas at 14, 30, and 60 dpi in EAE (each, n = 4) and control (n = 3) tissues. (E) Kcnq2 expression based on ISH in L4 mouse neurons at 14, 30, and 60 dpi in EAE, control, and Kcnq3-KO (each, n = 4) mice. (F) Kcnq3 expression (ISH) of mouse retinal specimens comprising the inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) revealed specific Kcnq3 expression in RGCs (yellow arrows). Plots show normalized Kcnq2/-3/-5 expression (qPCR) in sorted mouse NeuNhi RGC nuclei (control, n = 9; 15 dpi, n = 6; 30 dpi, n = 3; 60 dpi chronic, n = 3; 60 dpi rebound, n = 4). (G) Cartoon illustrates dysregulated neuron-OL K+ shuttling during inflammatory demyelination resulting in neuronal hyperexcitability, axonal swelling, and impaired neuronal function in addition to OL-Kir4.1 loss (colorless channels with dashed borders) and transient upregulation of nodal Kv7 channels. Scale bars: 100 μm (A and F); 20 μm (C–E). Original magnification, ×63 (enlarged insets in D). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (C–F).