Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis
Benjamin Schattling, … , Dirk Isbrandt, Manuel A. Friese
Benjamin Schattling, … , Dirk Isbrandt, Manuel A. Friese
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e89810. https://doi.org/10.1172/jci.insight.89810.
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Research Article Neuroscience

Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis

Abstract

Counteracting the progressive neurological disability caused by neuronal and axonal loss is the major unmet clinical need in multiple sclerosis therapy. However, the mechanisms underlying irreversible neuroaxonal degeneration in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are not well understood. A long-standing hypothesis holds that the distribution of voltage-gated sodium channels along demyelinated axons contributes to neurodegeneration by increasing neuroaxonal sodium influx and energy demand during CNS inflammation. Here, we tested this hypothesis in vivo by inserting a human gain-of-function mutation in the mouse NaV1.2-encoding gene Scn2a that is known to increase NaV1.2-mediated persistent sodium currents. In mutant mice, CNS inflammation during EAE leads to elevated neuroaxonal degeneration and increased disability and lethality compared with wild-type littermate controls. Importantly, immune cell infiltrates were not different between mutant EAE mice and wild-type EAE mice. Thus, this study shows that increased neuronal NaV1.2 activity exacerbates inflammation-induced neurodegeneration irrespective of immune cell alterations and identifies NaV1.2 as a promising neuroprotective drug target in multiple sclerosis.

Authors

Benjamin Schattling, Walid Fazeli, Birgit Engeland, Yuanyuan Liu, Holger Lerche, Dirk Isbrandt, Manuel A. Friese

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Figure 1

Generation and characterization of Scn2aA263V channelopathy mice.

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Generation and characterization of Scn2aA263V channelopathy mice. (A) Sc...
(A) Scheme of the targeting strategy of knockin mice carrying the human p.Ala263Val gain-of-function mutation in the Scn2a gene (left), and a representative image of PCR genotyping of wild-type, heterozygous (M/+), and homozygous (M/M) knockin animals (right). The lanes are from the same gel but were noncontiguous. (B) Quantitative real-time PCR of mouse Scn2a transcripts normalized to TATA-box-binding protein transcripts from wild-type and M/+ mutant whole spinal cord (n = 2 per group) or whole spleen homogenates (n = 2 per group). ΔCT values were arbitrarily calibrated to CNS cDNA of wild-type mice as the standard value of 1. Data are shown as mean ± SEM. (C) Western blot of cortical cell membranes from wild-type and M/+ mice at 3 weeks of age, demonstrating comparable abundance of NaV1.2 protein. The lanes are from the same gel but were noncontiguous. (D) Representative traces of current-clamp recordings from P10 to P12 hippocampal CA1 pyramidal neurons of wild-type and M/+ mice (injected currents from bottom to top trace in nA: –0.05; –0.025; 0.1; 0.225; 0.3). (E) Number of evoked action potentials plotted against the injected current. Wild-type: n = 10 cells from 2 animals; M/+: n = 15 cells from 3 animals. Data are shown as mean ± SEM.; 2-way analysis of variance (P = 0.0037 for genotype effect) was used for statistical analysis; **P < 0.01.