title: Reduced endplate currents underlie motor unit dysfunction in canine motor neuron disease.
abstract: Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant degenerative disorder of motor neurons. In homozygous animals, motor units produce decreased force output and fail during repetitive activity. Previous studies suggest that decreased efficacy of neuromuscular transmission underlies these abnormalities. To examine this, we recorded muscle fiber endplate currents (EPCs) and found reduced amplitudes and increased failures during nerve stimulation in homozygotes compared with wild-type controls. Comparison of EPC amplitudes with muscle fiber current thresholds indicate that many EPCs from homozygotes fall below threshold for activating muscle fibers but can be raised above threshold following potentiation. To determine whether axonal abnormalities might play a role in causing motor unit dysfunction, we examined the postnatal maturation of axonal conduction velocity in relation to the appearance of tetanic failure. We also examined intracellularly labeled motor neurons for evidence of axonal neurofilament accumulations, which are found in many instances of motor neuron disease including HCSMA. Despite the appearance of tetanic failure between 90 and 120 days, average motor axon conduction velocity increased with age in homozygotes and achieved adult levels. Normal correlations between motor neuron properties (including conduction velocity) and motor unit properties were also observed. Labeled proximal motor axons of several motor neurons that supplied failing motor units exhibited little or no evidence of axonal swellings. We conclude that decreased release of transmitter from motor terminals underlies motor unit dysfunction in HCSMA and that the mechanisms determining the maturation of axonal conduction velocity and the pattern of correlation between motor neuron and motor unit properties do not contribute to the appearance or evolution of motor unit dysfunction.
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Rich
authors.forename: Robert F
authors.initials: RF
authors.lastname: Waldeck
authors.forename: Linda C
authors.initials: LC
authors.lastname: Cork
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Balice-Gordon
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Fyffe
authors.forename: Xueyong
authors.initials: X
authors.lastname: Wang
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cope
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Pinter
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology; D004056:Differential Threshold; D004283:Dog Diseases / Q000235:genetics* / Q000503:physiopathology*; D004285:Dogs; D006720:Homozygote; D009045:Motor Endplate / Q000503:physiopathology*; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009134:Muscular Atrophy, Spinal / Q000662:veterinary*; D009431:Neural Conduction / Q000502:physiology; D013997:Time Factors