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Axonal conduction and injury in multiple sclerosis: the role of sodium channels

Nature Reviews Neuroscience volume 7, pages 932–941 (2006)Cite this article

Key Points

  • Multiple sclerosis (MS) is characterized by multiple neurological deficits reflecting lesions in multiple parts of the CNS. It has a relapsing–remitting course in some patients, and a progressive course in others.

  • Remissions in MS occur in the context of demyelination of CNS axons, which causes conduction failure, followed by restoration of conduction due to the expression of voltage-gated sodium channels (probably Nav1.2 channels) along denuded axon regions that previously lacked Na+ channels.

  • Disease progression (acquisition of persistent, non-remitting neurological deficits) in MS is due, in large part, to degeneration of axons in the CNS.

  • Sustained Na+ influx through Na+ channels (probably Nav1.6 channels) seems to drive reverse Na+/Ca2+ exchange, which imports injurious levels of Ca2+ into axons in MS, contributing to axonal degeneration.

  • Aberrant expression of sensory neuron specific Nav1.8 channels in cerebellar Purkinje neurons in MS appears to perturb their firing patterns. This might contribute to loss of coordination in MS.

  • Sodium channels also seem to have a role in the activation of, and phagocytosis by, macrophages and microglia in MS.

  • The identification of distinct pathophysiological roles of different Na+ channel isoforms suggests that it might be possible to develop therapies that target these channel isoforms so as to prevent axonal degeneration, reduce inflammation and/or ameliorate neuronal mistuning in MS.

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.

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Figure 1: Na+ channel organization of myelinated and demylinated axons.
Figure 2: Model of functional effects of expression of Nav1.2 and Nav1.6 channels along demyelinated axons.
Figure 3: Nav1.6 and Nav1.2 channel expression along demyelinated axons in active MS lesions.
Figure 4: Sensory neuron specific Na+ channel Nav1.8 is aberrantly expressed within cerebellar Purkinje neurons in MS and its experimental models.
Figure 5: Na+ channels are present in EAE and MS, and contribute to microglia/macrophage activation and function.

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Acknowledgements

Research in the author's laboratory has been supported, in part, by grants from the National Multiple Sclerosis Society and the Medical Research Service and Rehabilitation Research Service, the Department of Veteran Affairs, and by gifts from Destination Cure and the Nancy Davis Foundation. The Neuroscience and Regeneration Research Center is a Collaboration of the Paralyzed Veterans of America and the United Spinal Association with Yale University.

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  1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, 06510, Connecticut

    Stephen G. Waxman

  2. Rehabilitation Research Center, Veterans Affairs Medical Center, West Haven, 06516, Connecticut, USA

    Stephen G. Waxman

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Correspondence to Stephen G. Waxman.

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Glossary

Nodes of Ranvier

Small gaps in the myelin sheath along myelinated fibres. Nodes of Ranvier extend ∼1 μm along the fibre, and are separated by segments of myelin that extend for tens or, more commonly, hundreds of micrometres.

Internodal domains

Regions of the axon between the nodes of Ranvier.

Saltatory conduction

A process of rapid impulse conduction that is conferred on axons by myelin sheaths, in which the action potential leaps discontinously and rapidly from one node of Ranvier to the next.

Impedance mismatch

A phenomenon in which, owing to non-uniform properties, there is a sudden drop in electrical resistance or rise in capacitance along a cable or nerve fibre. Impedance mismatch occurs at the border between normally myelinated and demyelinated parts of axons in disorders such as multiple sclerosis, and contributes to conduction failure.

Capacitative shield

The electrical shield provided by the myelin that surrounds the axon, which prevents loss of current through the membrane capacitance of the axon.

Longitudinal current analysis

A method in which extracellular electrodes are used to measure electrical currents as they flow along nerve fibres and, thereby, to infer the presence of nodes or foci of node-like membrane.

Electron microprobe

A non-invasive tool that permits the measurement of the elemental composition of tissues.

Paranodal domain

The part of the axon, at the ends of the internodes, where the axon and the myelin form a relatively tight seal (the paranodal junction).

Plaque load

An aggregate measure of the number and volume of lesions in a brain with multiple sclerosis.

Ataxia

Loss of coordination of muscle movements, produced most commonly by dysfunction of the cerebellum (cerebellar ataxia) or defective sensory input (sensory ataxia).

Channelopathies

Disorders due to mutations of ion channels (inherited channelopathies), or due to altered channel function attributable to exposure to toxins or antibodies, or to dyregulated channel expression after tissue injury (acquired channelopathies).

Electrogenesis

The production of electrical signals — for example, action potentials — by cells such as neurons.

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Waxman, S. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 7, 932–941 (2006). https://doi.org/10.1038/nrn2023

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