Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination.
Demyelination results in conduction block through changes in passive cable properties of an axon and in the expression and localization of axonal ion channels. We show here that adult-onset chronic demyelination, such as occurs in demyelinating disorders and after nerve injury, alters the complement of axonal voltage-dependent Na+ (Nav) channel isoforms and their localization. As a model, we used heterozygous transgenic mice with two extra copies of the proteolipid protein gene (Plp/-). Retinal ganglion cell axons in these mice myelinate normally, with young Plp/- and wild-type mice expressing Nav1.2 at low levels, whereas Nav1.6 is clustered in high densities at nodes of Ranvier. At 7 months of age, however, Plp/- mice exhibit severe demyelination and oligodendrocyte cell death, leading to a profound reduction in Nav1.6 clusters, loss of the paranodal axoglial apparatus, and a marked increase in Nav1.2. We conclude that myelin is crucial not only for node of Ranvier formation, but also to actively maintain the proper localization and complement of distinct axonal Nav channel isoforms throughout life. The altered Nav channel isoform localization and complement induced by demyelination may contribute to the pathophysiology of demyelinating disorders and nerve injury.
Rasband
Matthew N
MN
Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, Stony Brook, New York, USA. Rasband@uchc.edu
Kagawa
Tetsushi
T
Park
Eunice W
EW
Ikenaka
Kazuhiro
K
Trimmer
James S
JS
D000375:Aging; D000818:Animals; D001369:Axons / Q000378:metabolism*; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006579:Heterozygote; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009900:Optic Nerve / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011901:Ranvier's Nodes / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; D018991:Myelin Proteolipid Protein; D010455:Peptides; D020033:Protein Isoforms; D015222:Sodium Channels