Co‐localization of sodium channel Nav1.6 and the sodium–calcium exchanger at sites of axonal injury in the spinal cord in EAE

• Published in: Brain (London, England : 1878) Vol. 127; no. 2; pp. 294 - 303
• Main Authors: Craner, Matthew J., Hains, Bryan C., Lo, Albert C., Black, Joel A., Waxman, Stephen G.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2004; Oxford Publishing Limited (England)
• Subjects: Amyloid beta-Protein Precursor - metabolism; Animals; axonal injury; Axons - metabolism; Axons - pathology; Biological and medical sciences; EAE = experimental allergic encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; experimental allergic encephalomyelitis; Female; Male; MBP = myelin basic protein; Medical sciences; Mice; MOG = myelin oligodendrocyte glycoprotein; multiple sclerosis; Myelin Sheath - pathology; NAV1.2 Voltage-Gated Sodium Channel; NAV1.6 Voltage-Gated Sodium Channel; NCX = sodium/calcium exchanger; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Tissue Proteins - metabolism; Neurology; NO = nitric oxide; sodium channel; Sodium Channels - metabolism; Sodium-Calcium Exchanger - metabolism; sodium/calcium exchanger; Spinal Cord - metabolism; Spinal Cord - pathology; TTX = tetrodotoxin; β‐APP = β‐amyloid precursor protein; Immunopathology; Allergy; Spinal cord; Multiple sclerosis; Nervous system diseases; Calcium; Encephalomyelitis; Central nervous system; experimental allergic encephalomyelitis; Cerebral disorder; Inflammatory disease; axonal injury; Sodium; sodium channel; Central nervous system disease; sodium/calcium exchanger; Spinal cord disease
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awh032

Axonal degeneration contributes to the development of non‐remitting neurological deficits and disability in multiple sclerosis, but the molecular mechanisms that underlie axonal loss in multiple sclerosis are not clearly understood. Studies of white matter axonal injury have demonstrated that voltage‐gated sodium channels can provide a route for sodium influx into axons that triggers reverse operation of the Na+/Ca2+ exchanger (NCX) and subsequent influx of damaging levels of intra‐axonal calcium. The molecular identities of the involved sodium channels have, however, not been determined. We have previously demonstrated extensive regions of diffuse expression of Nav1.6 and Nav1.2 sodium channels along demyelinated axons in experimental allergic encephalomyelitis (EAE). Based on the hypothesis that the co‐localization of Nav1.6 and NCX along extensive regions of demyelinated axons may predispose these axons to injury, we examined the expression of myelin basic protein, Nav1.2, Nav1.6, NCX and β‐amyloid precursor protein (β‐APP), a marker of axonal injury, in the spinal cord dorsal columns of mice with EAE. We demonstrate a significant increase in the number of demyelinated axons demonstrating diffuse Nav1.6 and Nav1.2 sodium channel immunoreactivity in EAE (92.2 ± 2.1% of β‐APP positive axons were Nav1.6‐positive). Only 38.0 ± 2.9% of β‐APP positive axons were Nav1.2 positive, and 95% of these co‐expressed Nav1.6 together with Nav1.2. Using triple‐labelled fluorescent immunohistochemistry, we demonstrate that 73.5 ± 4.3% of β‐APP positive axons co‐express Nav1.6 and NCX, compared with 4.4 ± 1.0% in β‐APP negative axons. Our results indicate that co‐expression of Nav1.6 and NCX is associated with axonal injury in the spinal cord in EAE.