Reduced Endplate Currents Underlie Motor Unit Dysfunction in Canine Motor Neuron Disease

• Published in: Journal of neurophysiology Vol. 88; no. 6; pp. 3293 - 3304
• Main Authors: Rich, Mark M, Waldeck, Robert. F, Cork, Linda C, Balice-Gordon, Rita J, Fyffe, Robert E. W, Wang, Xueyong, Cope, Timothy C, Pinter, Martin J
• Format: Journal Article
• Language: English
• Published: United States Am Phys Soc 01-12-2002
• Subjects: Aging - physiology; Animals; Axons - physiology; Differential Threshold; Dog Diseases - genetics; Dog Diseases - physiopathology; Dogs; Homozygote; Motor Endplate - physiopathology; Muscle Contraction; Muscle Fibers, Skeletal - physiology; Muscle, Skeletal - physiopathology; Muscular Atrophy, Spinal - veterinary; Neural Conduction - physiology; Time Factors
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00270.2002

  1 Department of Physiology and
  2 Department of Neurology, Emory University
School of Medicine, Atlanta, Georgia 30322;
  3 Department of Neurobiology and Anatomy, Medical
College of Pennsylvania, Hahnemann University, Philadelphia,
Pennsylvania 19129;   4 Department of Comparative
Medicine, Stanford University School of Medicine, Stanford, California
94305-5410;   5 Department of Neuroscience,
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104-6074; and   6 Department of
Anatomy, Wright State University School of Medicine, Dayton, Ohio 45435
Rich, Mark M.,
Robert. F. Waldeck,
Linda
C. Cork,
Rita J. Balice-Gordon,
Robert E. W. Fyffe,
Xueyong Wang,
Timothy C. Cope, and
Martin J. Pinter.
Reduced Endplate Currents Underlie Motor Unit Dysfunction in
Canine Motor Neuron Disease. J. Neurophysiol. 88: 3293-3304, 2002. 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.