Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
Hannah Kapell, et al.
Hannah Kapell, et al.
View: Text | PDF
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

×

Figure 2

KCNQ3 dysregulation in cortical and retinal MS tissues.

Options: View larger image (or click on image) Download as PowerPoint
KCNQ3 dysregulation in cortical and retinal MS tissues. (A) Uniform man...
(A) Uniform manifold approximation and projection (UMAP) plot visualizes clustering of human excitatory (EN) and inhibitory (IN) cortical neurons based on a published snRNA-Seq data set (12). (B) Normalized KCNQ2/-3/-5 expression in control (Ctrl) and MS human cortical neurons. (C) Spatial KCNQ3 expression (ISH) in the human cortex. (D) Violin plots visualize average KCNQ2/-3/-5 expression levels (snRNA-Seq, A) in control neurons (n = 5; green dashed line) and representative MS samples from patients with various disease durations. (E) KCNQ3 ISH in human CGM and MS NAGM and DMGM lesion areas based on MOG IR. DL, deep layers. (F) Correlation of nucleus- and cytoplasm-associated KCNQ3 transcript counts within the same cell in human cortical tissues (ISH) from CGM (n = 35 areas, n = 5 patients), NAGM (n = 27 areas, n = 8 patients) and DMGM (n = 34 areas, n = 8 patients). (G) KCNQ3 upregulation in DMGM (ISH) independent of neuronal density. (H) Gradual loss of mean KCNQ3 expression in MS GM tissues (ISH) from patients with a prolonged MS disease duration approached CGM expression levels (n = 5, green dashed line). (I) Unsupervised trajectory inference of upper L2/-3 neuron branch and nuclei distribution along the trajectory (compare with Supplemental Figure 3, E and F) based on MS disease duration, demyelination (DM) extent, and lesion stage. (J and K) Pseudotime-dependent KCNQ2/-3/-5 expression in relation to disease duration and demyelination based on MOG IR. (L) Neuronal KCNQ2/-3/-5 expression grouped by lesion stage. (M) Sorting of retinal nuclei based on NeuN IR. (N) Normalized KCNQ2/-3/-5 expression by qPCR in human RGC nuclei (controls, n = 6; MS, n = 7). Scale bars: 500 μm (C); 100 μm (E). *P < 0.05, **P < 0.01, ***P < 0.001, by Wilcoxon rank-sum test with Bonferroni’s correction (B); generalized linear model by Wald test with Benjamini and Hochberg correction (D and L); simple linear regression (F and H); Kruskal-Wallis test (G); and mixed-effects model with Geisser-Greenhouse correction and Šidák’s multiple-comparison test (N). ACA, acute chronic active; CI, chronic inactive.