REVIEWS Axonal conduction and injury in multiple sclerosis: the role of sodium channels Stephen G. Waxman Abstract | Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. Recent studies have implicated specific sodium channel isoforms as having an important role in several aspects of the pathophysiology of MS, including the restoration of impulse conduction after demyelination, axonal degeneration and the mistuning of Purkinje neurons that leads to cerebellar dysfunction. By manipulating the activity of these channels or their expression, it might be possible to develop new therapeutic approaches that will prevent or limit disability in MS. Nodes of Ranvier Multiple sclerosis (MS) is the most common neurological contribute to axonal degeneration, and the possibility of + Small gaps in the myelin cause of disability in young adults in industrialized societies. a role for a third Na channel isoform in the mistuning of sheath along myelinated fibres. It is usually diagnosed between the ages of 20 and 40, and cerebellar Purkinje neurons, which perturbs the pattern Nodes of Ranvier extend ~1 is called ‘multiple’ sclerosis because most patients have of activity of these cells. μm along the fibre, and are separated by segments of multiple attacks separated both in time and in space, in + myelin that extend for tens or, which different parts of the CNS can be involved (for Na channels and axonal conduction more commonly, hundreds of example, involvement of the optic nerve can cause uni- The disease process in MS attacks myelinated axons, micrometres. lateral visual loss, whereas involvement of spinal sensory denuding them of myelin or causing them to degener- tracts can cause numbness). Early in its course, MS often ate. Normal myelinated axons exhibit a clustering of Internodal domains + μ –2 Regions of the axon between displays a relapsing–remitting pattern, with patients losing Na channels (~1,000 m ) in the axon membrane the nodes of Ranvier. functions such as vision or motor function, then recover- at the nodes of Ranvier, with a much lower density ing these capabilities during remissions. Later in some (< 25 channels μm–2) in internodal domains where the Saltatory conduction patients (secondary progressive MS), or at the beginning axon is covered by myelin1,2. This arrangement (FIG. 1a) A process of rapid impulse saltatory conduction conduction that is conferred on of disease onset in others (primary progressive MS), there supports in the normal myelinated axons by myelin sheaths, in is cumulative acquisition of neurological deficits which axon. However, it is less well-suited to the functional which the action potential do not remit. Although the cause of MS is unknown, and needs of the demyelinated axon, in which impedance leaps discontinously and multiple etiologies including autoimmunity, infectious mismatch and loss of the myelin capacitative shield permit rapidly from one node of agents, environmental triggers and hereditary factors have current to be dissipated through formerly myelinated Ranvier to the next. been proposed, there is substantial evidence to indicate portions of the axon membrane where Na+ channel that dysregulated immune responses, including immune density is low, impairing the conduction of action mechanisms directed against myelin proteins, have a role potentials (FIG. 1b). Department of Neurology and in triggering disease onset. Following the loss of myelin in MS, remyelination does Center for Neuroscience and Recent studies have identified changes in the expres- not always occur and in many lesions the myelin is not Regeneration Research, Yale sion pattern of specific Na+ channel isoforms as an impor- replaced. Surprisingly, although demyelination causes School of Medicine, New tant contributor to remission and progression in MS, and symptoms such as visual loss (when the optic nerve is Haven, Connecticut 06510, + and the Rehabilitation there is evidence suggesting that aberrantly expressed Na involved) or weakness (when the corticospinal tract Research Center, Veterans channels might also contribute to cerebellar dysfunction is involved), remissions can occur in the absence of remy- Affairs Medical Center, in MS. In this article, I discuss the multiple roles of Na+ elination. For example, vision can recover in some patients West Haven, Connecticut channels in the pathophysiology of MS, including the in which demyelination affects a substantial length 06516, USA. + e-mail: adaptive role of some Na channel isoforms in restor- (a centimetre or more, thereby encompassing the [email protected] ing conduction in chronically demyelinated axons, the territory of many myelin segments) of all the axons doi:10.1038/nrn2023 mal adaptive role of other Na+ channel isoforms that within the optic nerve3. Recovery of clinical function in 932 | DECEMBER 2006 | VOLUME 7 www.nature.com/reviews/neuro © 2006 Nature Publishing Group REVIEWS a Nav1.6 Myelinated Caspr Node internode ? 5 μm b ? c ? d 10 μm Figure 1 | Na+ channel organization of myelinated and demylinated axons. a | Voltage-gated sodium (Nav) channels, now identified as the Nav1.6 isoform, are aggregated at a high density in the normal axon membrane at the nodes of Ranvier, but are sparse in the paranodal and internodal axon membranes under the myelin. Right panel shows clustering of Nav1.6 channels (red) at a node of Ranvier, bounded by Caspr (a constituent of the paranodal apparatus; green) in paranodal regions, in a normal myelinated axon. Fluorescence and differential contrast images are merged to show the myelin sheath. b | The acutely demyelinated axon has a low Na+ channel density, a factor that contributes to conduction failure. c | Some demyelinated axons acquire higher-than-normal densities of Na+ channels in regions where myelin has been lost, supporting the restoration of conduction that contributes to clinical remissions. Extensive expression of Nav1.6 Impedance mismatch (red, upper right panel) and Nav1.2 channels ( red, lower right panel) along optic nerve axons (arrows) in experimental A phenomenon in which, owing autoimmune encephalomyelitis (EAE) is shown. d | Degeneration of axons also occurs in multiple sclerosis, and produces to non-uniform properties, non-remitting, permanent loss of function. Images in part c reproduced, with permission, from REF. 34 © (2003) Oxford there is a sudden drop in Univ. Press. electrical resistance or rise in capacitance along a cable or nerve fibre. Impedance + mismatch occurs at the border cases such as this requires the restoration of secure action Na channels and axonal degeneration between normally myelinated potential conduction along at least some of the demyeli- Although largely eclipsed by an emphasis on demyelina- and demyelinated parts of nated axons. Setting the stage for an understanding of the tion, it has been appreciated since the time of Charcot axons in disorders such as role of Na+ channels in this process, an early longitudinal that, in addition to becoming demyelinated, some axons multiple sclerosis, and contributes to conduction current analysis showed that some chronically demyelinated degenerate in MS. Recent studies have focused new failure. axons can recover the ability to conduct action potentials attention on axonal degeneration in MS (FIG. 1d), and in a continuous manner4, and early cytochemical studies have underscored its frequency and occurrence early Capacitative shield showed that, after demyelination, the denuded axon in the course of the disease9,10. Importantly, studies in The electrical shield provided by the myelin that surrounds membrane can develop higher-than-normal densities of animal models and in human MS patients have shown + 5 the axon, which prevents loss Na channels . Immunocytochemical studies using pan- that axonal loss produces non-remitting, persistent of current through the specific Na+ channel antibodies6,7 subsequently confirmed neurological deficits11,12. This has led to considerable membrane capacitance of the the appearance of increased numbers of Na+ channels interest in the development of protective strategies aimed axon. in experimentally demyelinated axons. Saxitoxin bind- at preventing degeneration of axons, and thereby slowing Longitudinal current ing studies also demonstrated a fourfold increase in the or halting the progression of disability in MS. analysis number of Na+ channels in demyelinated lesions from MS The available evidence suggests that Na+ channels are A method in which extracellular patients8. Taken together, these results indicated that Na+ important participants in axonal degeneration in MS electrodes are used to measure channel expression is increased in at least some demy- (FIG. 2). As described below, there is evidence for energy electrical currents as they flow (FIG. 1c) along nerve fibres and, thereby, elinated axons . However, these early studies did failure within the CNS in MS. Early studies on white + to infer the presence of nodes not reveal the molecular identity of the new axonal Na matter tracts in vitro used anoxia, which produces energy or foci of node-like membrane. channels along demyelinated axons. failure, as a highly reproducible, quantifiable insult, and NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | DECEMBER 2006 | 933 © 2006 Nature Publishing Group REVIEWS to have a protective effect in an experimental model of Microglia MS, experimental autoimmune encephalomyelitis (EAE), where they prevent degeneration of CNS axons, maintain axonal conduction and improve clinical