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Motor Neuron Degeneration Induced by Excitotoxin Agonists Has Features in Common with those Seen in the SOD-1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Chrysanthy Ikonomidou MD, Yue Qin Qin MD, Joann Labruyere, John W. Olney MD
DOI: http://dx.doi.org/10.1097/00005072-199602000-00010 211-224 First published online: 1 February 1996


A superoxide dismutase 1 (SOD-1) genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of ionotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day-old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neurons becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation of non-NMDA glutamate receptors.

Key Words
  • AMPA
  • Amyotrophic lateral sclerosis
  • DL-homocysteic acid
  • Excitotoxicity
  • Kainic acid
  • NMDA
  • SOD-1 transgenic mouse