title: Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B.
abstract: Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/- showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle. This progressive functional impairment was in contrast to the mild demyelinating neuropathy of the tibial nerve revealed by histology. "Threshold-tracking" studies showed impaired motor axon excitability in P0+/- from 3months. With time, there was a progressive reduction in threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus associated with increasing resting I/V slope and increasing strength-duration time constant. These depolarizing features in excitability in P0+/- as well as the reduced CMAP amplitude were absent in P0+/- NaV1.8 knockouts, and could be acutely reversed by selective pharmacologic block of NaV1.8 in P0+/-. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na(+) current in P0+/-. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing conduction failure in CMT1B, and that motor axon dysfunction in demyelinating neuropathy is pharmacologically reversible.
authors.affiliation: Institute of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Department of Clinical Neurophysiology, The Neuroscience Center, Copenhagen University Hospital (Rigshospitalet), Denmark.
authors.forename: Mette R
authors.initials: MR
authors.lastname: Rosberg
authors.affiliation: Institute of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Department of Clinical Neurophysiology, The Neuroscience Center, Copenhagen University Hospital (Rigshospitalet), Denmark.
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.affiliation: Neurology, Developmental Neurobiology, University of Würzburg, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Klein
authors.affiliation: Genomic Medicine, Copenhagen University Hospital (Rigshospitalet), Denmark.
authors.forename: Finn Cilius
authors.initials: FC
authors.lastname: Nielsen
authors.affiliation: Neurology, Developmental Neurobiology, University of Würzburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
authors.affiliation: University of Colorado, Denver, Physiology and Biophysics, United States.
authors.forename: S Rock
authors.initials: SR
authors.lastname: Levinson
authors.affiliation: Institute of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Department of Clinical Neurophysiology, The Neuroscience Center, Copenhagen University Hospital (Rigshospitalet), Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Krarup
authors.affiliation: Institute of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Department of Clinical Neurophysiology, The Neuroscience Center, Copenhagen University Hospital (Rigshospitalet), Denmark.
authors.forename: Mihai
authors.initials: M
authors.lastname: Moldovan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism / Q000473:pathology*; D003711:Demyelinating Diseases / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D018993:Myelin P0 Protein / Q000235:genetics; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009431:Neural Conduction / Q000502:physiology; D013979:Tibial Nerve / Q000378:metabolism / Q000473:pathology
chemical_list: D018993:Myelin P0 Protein; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse
keywords: Excitability; Internode; Ion channels; Nerve activity; Node of Ranvier