Functional changes in genetically dysmyelinated spinal cord axons of shiverer mice: role of juxtaparanodal Kv1 family K+ channels.
Axonal dysfunction after spinal cord injury (SCI) and other types of neurotrauma is associated with demyelination and exposure of juxtaparanodal K+ channels. In this study, sucrose gap electrophysiology using selective and nonselective K+ channel blockers, confocal immunohistochemistry, and Western blotting were used to study the role of Kv1.1 and Kv1.2 K+ channel subunits in dysmyelination-induced spinal cord axonal dysfunction in shiverer mice, which lack the gene encoding myelin basic protein (MBP) and exhibit incomplete myelin sheath formation on CNS axons. The shiverer spinal cord axons exhibited smaller amplitude of compound action potentials (CAPs), reduced conduction velocity, reduced excitability, and greater degree of high-frequency conduction failure. The "fast" K+ channel blocker 4-aminopyridine, the toxin DTX-I, which targets the Kv1.1 and Kv1.2, but not DTX- K, which has higher selectivity for Kv1.1, increased the amplitude and area of CAPs of shiverer mice spinal cord axons but had insignificant effects in wild-type mice. Confocal immunohistochemistry showed that, unlike wild-type mice, which have a precise juxtaparanodal localization of the Kv1.l and Kv1.2 K+ channel subunits, shiverer mouse axons displayed a dispersed distribution of these subunits along the internodes. In contrast, the Kv1.l and Kv1.2 subunits, Na+ channels remained highly localized to the nodal regions. Western blotting showed an increased expression of Kv 1.1 and 1.2 in the shiverer mouse spinal cord. These results provide evidence that the neurological deficits associated with myelin deficiency reflect the altered distribution and expression of the K+ channel subunits Kv1.l and Kv1.2 along the internodes of spinal cord axons associated with the biophysical consequences caused by alterations in the myelin sheaths.
Sinha
Kusum
K
Div. of Cell and Molecular Biology, Univ. of Toronto, Toronto Western Hospital, Univ. Health Network, Rm. 4W-449, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada.
Karimi-Abdolrezaee
Soheila
S
Velumian
Alexander A
AA
Fehlings
Michael G
MG
D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D066298:In Vitro Techniques; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism*; D014018:Tissue Distribution
D051663:Kv1.2 Potassium Channel; D051662:Kv1.1 Potassium Channel