Activity-Driven Synaptic and Axonal Degeneration in Canine Motor Neuron Disease

• Published in: Journal of neurophysiology Vol. 92; no. 2; pp. 1175 - 1181
• Main Authors: Carrasco, Dario I, Rich, Mark M, Wang, Qingbo, Cope, Timothy C, Pinter, Martin J
• Format: Journal Article
• Language: English
• Published: United States Am Phys Soc 01-08-2004
• Subjects: Animals; Axons; Dogs; Motor Endplate - physiopathology; Motor Neurons; Muscle Denervation; Muscle, Skeletal - innervation; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - physiopathology; Nerve Degeneration; Nerve Regeneration; Neural Conduction; Neurofilament Proteins - metabolism; Neuromuscular Junction - physiopathology; Synapses; Tarsus, Animal; Time Factors
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00157.2004

1 Departments of Physiology and 2 Neurology, Emory University School of Medicine, Atlanta, Georgia 30322
Submitted 17 February 2004;
accepted in final form 15 March 2004
The role of neuronal activity in the pathogenesis of neurodegenerative disease is largely unknown. In this study, we examined the effects of increasing motor neuron activity on the pathogenesis of a canine version of inherited motor neuron disease (hereditary canine spinal muscular atrophy). Activity of motor neurons innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by denervating close synergist muscles. In affected animals, 4 wk of synergist denervation accelerated loss of motor-unit function relative to control muscles and decreased motor axon conduction velocities. Slowing of axon conduction was greatest in the most distal portions of motor axons. Morphological analysis of neuromuscular junctions (NMJs) showed that these functional changes were associated with increased loss of intact innervation and with the appearance of significant motor axon and motor terminal sprouting. These effects were not observed in the MG muscles of age-matched, normal animals with synergist denervation for 5 wk. The results indicate that motor neuron action potential activity is a major contributing factor to the loss of motor-unit function and degeneration in inherited canine motor neuron disease.
Address for reprint requests and other correspondence: M. J. Pinter, Dept. of Physiology, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322 (E-mail: mpinter{at}physiol.emory.edu ).