AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo
Article first published online: 6 APR 2004
Journal of Neurochemistry
Volume 89, Issue 4, pages 988–997, May 2004
How to Cite
Corona, J. C. and Tapia, R. (2004), AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo. Journal of Neurochemistry, 89: 988–997. doi: 10.1111/j.1471-4159.2004.02383.x
- Issue published online: 13 APR 2004
- Article first published online: 6 APR 2004
- Received November 18, 2003; revised manuscript received January 9, 2004; accepted January 13, 2004.
- AMPA receptor;
- amyotrophic lateral sclerosis;
- motor neurons;
- spinal cord
The mechanisms of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS) are unknown, but glutamate-mediated excitotoxicity may be involved. To examine directly this idea in vivo, we have used microdialysis in the rat lumbar spinal cord and showed that four- to fivefold increases in the concentration of endogenous extracellular glutamate during at least 1 h, by perfusion with the glutamate transport inhibitor l-2,4-trans-pyrrolidine-dicarboxylate, elicited no motor alterations or MN damage. Stimulation of glutamate release with 4-aminopyridine induced transitory ipsilateral hindlimb muscular twitches but no MN damage. In contrast, perfusion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) did not modify glutamate levels but produced intense muscular spasms, followed by ipsilateral permanent hindlimb paralysis and a remarkable loss of MNs. These effects of AMPA were prevented by co-perfusion with the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline. Perfusion with NMDA or kainate produced no motor effects or MN damage. Thus, the elevation of endogenous extracellular glutamate in vivo due to blockade of its transport is innocuous for spinal MNs. Because this resistance is observed under the same experimental conditions in which MNs are highly vulnerable to AMPA, these results indicate that excitotoxicity due to this mechanism might not be an important factor in the pathogenesis of ALS.