Expression of Nav1.6 sodium channels by Schwann cells at neuromuscular junctions: role in the motor endplate disease phenotype.
In addition to their role in action potential generation and fast synaptic transmission in neurons, voltage-dependent sodium channels can also be active in glia. Terminal Schwann cells (TSCs) wrap around the nerve terminal arborization at the neuromuscular junction, which they contribute to shape during development and in the postdenervation processes. Using fluorescent in situ hybridization (FISH), immunofluorescence, and confocal microscopy, we detected the neuronal Nav1.6 sodium channel transcripts and proteins in TSCs in normal adult rats and mice. Nav1.6 protein co-localized with the Schwann cell marker S-100 but was not detected in the SV2-positive nerve terminals. The med phenotype in mice is due to a mutation in the SCN8A gene resulting in loss of Nav1.6 expression. It leads to early onset in postnatal life of defects in neuromuscular transmission with minimal alteration of axonal conduction. Strikingly, in mutant mice, the nonmyelinated pre-terminal region of axons showed abundant sprouting at neuromuscular junctions, and most of the alpha-bungarotoxin-labeled endplates were devoid of S-100- or GFAP-positive TSCs. Using specific antibodies against the Nav1.2 and Nav1.6 sodium channels, ankyrin G and Caspr 1, and a pan sodium channel antibody, we found that a similar proportion of ankyrin G-positive nodes of Ranvier express sodium channels in mutant and wild-type animals and that nodal expression of Nav1.2 persists in med mice. Our data supports the hypothesis that the lack of expression of Nav1.6 in Schwann cells at neuromuscular junctions might play a role in the med phenotype.
Musarella
Magali
M
INSERM, UMR 641, IFR Jean Roche, Marseille, France; Université de la Méditerranée,Faculté de Médecine Nord, Marseille, Cedex, France.
Alcaraz
Gisèle
G
Caillol
Ghislaine
G
Boudier
Jean-Louis
JL
Couraud
François
F
Autillo-Touati
Amapola
A
D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008818:Mice, Neurologic Mutants; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020511:Neuromuscular Junction Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D051381:Rats; D009418:S100 Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics
C094681:Ank3 protein, mouse; D017487:Ankyrins; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009418:S100 Proteins; C568253:Scn2A protein, rat; C000654500:Scn2a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels; C489614:Sv2a protein, mouse