Abstract
The molecular determinants of abnormal propagation of action potentials along axons and ectopic conductance in demyelinating diseases of the central nervous system, like multiple sclerosis (MS), are poorly defined. Widespread interruption of myelin occurs in several mouse models of demyelination, rendering them useful for research. Herein, considerable myelin loss is shown in the optic nerves of cuprizone-treated demyelinating mice. Immuno-fluorescence confocal analysis of the expression and distribution of voltage-activated K+ channels (KV1.1 and 1.2 α subunits) revealed their spread from typical juxta-paranodal (JXP) sites to nodes in demyelinated axons, albeit with a disproportionate increase in the level of KV1.1 subunit. Functionally, in contrast to monophasic compound action potentials (CAPs) recorded in controls, responses derived from optic nerves of cuprizone-treated mice displayed initial synchronous waveform followed by a dispersed component. Partial restoration of CAPs by broad spectrum (4-aminopyridine) or KV1.1-subunit selective (dendrotoxin K) blockers of K+ currents suggest enhanced KV1.1-mediated conductance in the demyelinated optic nerve. Biophysical profiling of K+ currents mediated by recombinant channels comprised of different KV1.1 and 1.2 stoichiometries revealed that the enrichment of KV1 channels KV1.1 subunit endows a decrease in the voltage threshold and accelerates the activation kinetics. Together with the morphometric data, these findings provide important clues to a molecular basis for temporal dispersion of CAPs and reduced excitability of demyelinated optic nerves, which could be of potential relevance to the patho-physiology of MS and related disorders.
Highlights
Multiple sclerosis (MS) is a polyfactorial, devastating disease of the central nervous system (CNS)
CNS demyelination was established in mice fed with cuprizone for 8 weeks
Analysis of brain sections stained for myelin with cresyl violet (CV) or luxol fast blue (LFB) revealed its depletion especially notable in white matter-rich structures such as corpus callosum, internal capsule, stripes of the caudate nucleus and cerebellar peduncle (Fig. 1A, B)
Summary
Multiple sclerosis (MS) is a polyfactorial, devastating disease of the central nervous system (CNS). Functional and developmental studies have indicated essential roles for myelin in the rapid conduction of action potentials along thick myelinated axons [3,4]. There is considerable but conflicting evidence suggesting a stabilizing influence of voltage-activated KV1 currents on the excitability and conductivity of central and peripheral axons [5,6,7]. Several studies assigned therapeutic effects of 4-AP to its inhibition of immune cell proliferation [12,16]. Such broad-spectrum effects hampers the utilisation of 4-AP for discriminatory restoration of the functionality of demyelinated axons without off target effects
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