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

A superoxide dismutase 1 (SOD-I) genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degener ation has been described in SOD-1 transgenic mice. Because an excitoto xic mechanism has been implicated in ALS, we undertook studies to prov ide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-I transge nic mice. Excitotoxin agonists selective for each of the three major t ypes 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 neuro ns, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely rese mbled those described in SOD-1 mice. These changes consist of massivel y swollen dendritic processes in the presence of well-preserved presyn aptic axon terminals; cell bodies of motor neurons tilled with vacuole s that originate both from endoplasmic reticulum and mitochondria; ple omorphic changes in mitochondria; axons of motor neurons becoming swol len proximally with accumulation of vacuoles, organelles, filaments, a nd degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS pa tients. These findings are consistent with the proposal that motor neu ron degeneration in ALS may be mediated by an excitotoxic process invo lving hyperactivation of non-NMDA glutamate receptors.