Na+ channel expression along axons in multiple sclerosis and its models

doi:10.1016/j.tips.2004.09.001

Trends in Pharmacological Sciences

Volume 25, Issue 11, November 2004, Pages 584-591

https://doi.org/10.1016/j.tips.2004.09.001 Get rights and content

Following the loss of myelin from axons in multiple sclerosis, some axons recover the ability to conduct impulses despite the absence of an insulating sheath, providing a basis for remission of clinical deficits. By contrast, other axons degenerate and contribute to non-remitting clinical deficits and, thus, disability. Investigations using laboratory models of multiple sclerosis indicate that altered expression of two distinct isoforms of Na⁺ channels underlies these two processes, and the study of human tissue reveals similar changes in multiple sclerosis.

Section snippets

Na_v1.2 and Na_v1.6 channels in normal and dysmyelinated axons

Within the normal nervous system at early stages before glial ensheathment, Na⁺ channels are present at a low density along the entire length of pre-myelinated axons [20]. It is now known that Na_v1.2 channels are distributed diffusely along non-myelinated axons 21, 22, 23, and support action potential conduction that is known to occur in pre-myelinated axons 24, 25. By contrast, Na_v1.6 channels cluster at the nodes at Ranvier in myelinated axons (Figure 1) [26]. Isoform-specific studies have

Na_v1.2 channels in demyelinated axons: EAE

The Na⁺ channel isoforms expressed along demyelinated axons have been identified recently in studies that used subtype-specific immunocytochemical methods and in situ hybridization to examine white matter axons in mice with EAE 28, 29. Na_v1.1 and Na_v1.3 channels were not detectable along axons in control or EAE animals; this is notable because Na_v1.3 channels are upregulated and expressed within dorsal root ganglion cells and their axons [30], and in higher-order nociceptive neurons within the

Na_v1.6 channels in injured axons: EAE

The activity of Na⁺ channels can trigger Ca²⁺-mediated injury of white matter axons, by providing a sustained Na⁺ influx that drives reverse (Ca²⁺-importing) activity of the Na⁺–Ca²⁺ exchanger [4]. The available evidence indicates that a persistent (non-inactivating) Na⁺ conductance is involved [5]. Na_v1.6 channels are known to produce a persistent current in many cell types and this current is larger than the persistent current produced by Na_v1.2 channels 35, 36, 37. Coexpression of Na_v1.6

Na_v1.2 and Na_v1.6 channels in demyelinated axons: MS

Although EAE is the most commonly studied animal model of MS, there is no model that perfectly mimics all of the features of the human disorder, and the question ‘which Na⁺ channels are expressed along demyelinated axons in MS?’ therefore requires the examination of human tissue. Such a study [38] has been carried out recently on post-mortem spinal cord and optic nerve tissue from patients with disabling secondary progressive MS and from controls, acquired via a rapid autopsy protocol [39]; the

What do Na_v1.2 channels do in demyelinated axons?

The widespread distribution of Na_v1.2 channels, extending for tens of microns along demyelinated but apparently uninjured axons in EAE and MS, is similar to the diffuse distribution of Na_v1.2 channels along pre-myelinated axons [23], in which action potential conduction is known to occur 24, 25. Na_v1.2 channels are also present along non-myelinated axons within the CNS 22, 42, 43 where they appear to support action potential conduction.

Na_v1.6 channels appear particularly well suited to support

What do Na_v1.6 channels do in demyelinated axons?

Rapidly inactivating Na⁺ current would not be expected to produce the sustained influx of Na⁺ that is needed to drive reverse Na⁺–Ca²⁺ exchange and, as described earlier, a persistent Na⁺ conductance has been shown to have a prominent role in the triggering of reverse Na⁺–Ca²⁺ exchange and resultant Ca²⁺ entry that results in injury of myelinated axons 4, 5. Na_v1.6 channels produce a persistent Na⁺ current that becomes larger with depolarization 35, 36. Patch clamp studies on neurons expressing

Mapping the Na⁺ channels in MS

The molecular identities and distribution of the Na⁺ channels that are deployed in demyelinated and degenerating CNS axons are now being delineated both in animal models of MS and in MS itself. Interestingly, the two Na⁺ channel isoforms that have been detected thus far, Na_v1.2 and Na_v1.6, show different patterns of distribution: Na_v1.2 channels tend to be present in axons that are β-APP-negative (i.e. in axons that do not display signs of injury), whereas Na_v1.6 channels tend to be expressed

Acknowledgements

Research described in this article was supported, in part, by grants from the National Multiple Sclerosis Society and the Medical Research Service and Rehabilitation Research Service, 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. M.J.C. thanks Medical Director General, UK for support.

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Trends in Pharmacological Sciences

Na+ channel expression along axons in multiple sclerosis and its models

Section snippets

Nav1.2 and Nav1.6 channels in normal and dysmyelinated axons

Nav1.2 channels in demyelinated axons: EAE

Nav1.6 channels in injured axons: EAE

Nav1.2 and Nav1.6 channels in demyelinated axons: MS

What do Nav1.2 channels do in demyelinated axons?

What do Nav1.6 channels do in demyelinated axons?

Mapping the Na+ channels in MS

Acknowledgements

Neuroscience

Lancet Neurol.

Brain Res.

Neuron

Neuron

Neuron

Neuron

Neuron

Neuron

Brain Res.

Mol. Brain Res.

Demyelinating diseases: New pathological insights, new therapeutic targets

New Engl. J. Med.

Axonal transection in the lesions of multiple sclerosis

New Engl. J. Med.

Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time

Brain

Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na+-Ca2+ exchanger

J. Neurosci.

Noninactivating, tetrodotoxin-sensitive Na+ conductance in rat optic nerve axons

Proc. Natl. Acad. Sci. U. S. A.

Tertiary and quaternary local anesthetics protect CNS white matter from anoxic injury at concentrations that do not block excitability

J. Neurophysiol.

Anoxic injury in the rat spinal cord: pharmacological evidence for multiple steps in Ca2+ -dependent injury of the dorsal columns

J. Neurotrauma

Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury

J. Neurosci.

Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration

Ann. Neurol.

Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo

J. Neurophysiol.

Axonal protection using flecainide in experimental autoimmune encephalomyelitis

Ann. Neurol.

Reorganization of the axonal membrane of demyelinated nerve fibers: morphological evidence

Science

Disruption and reorganization of sodium channels in experimental allergic neuritis

Muscle Nerve

The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination

J. Physiol.

Na⁺ channel expression along axons in multiple sclerosis and its models

Na_v1.2 and Na_v1.6 channels in normal and dysmyelinated axons

Na_v1.2 channels in demyelinated axons: EAE

Na_v1.6 channels in injured axons: EAE

Na_v1.2 and Na_v1.6 channels in demyelinated axons: MS

What do Na_v1.2 channels do in demyelinated axons?

What do Na_v1.6 channels do in demyelinated axons?

Mapping the Na⁺ channels in MS

Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na⁺ channels and Na⁺-Ca²⁺ exchanger

Noninactivating, tetrodotoxin-sensitive Na⁺ conductance in rat optic nerve axons

Anoxic injury in the rat spinal cord: pharmacological evidence for multiple steps in Ca²⁺ -dependent injury of the dorsal columns