Motor neuron (MN) degeneration is the pathological hallmark of MN diseases, a group of
neurodegenerative disorders clinically manifested as muscle
fasciculations and
hyperreflexia, followed by
paralysis, respiratory failure, and death. Ample evidence supports a role of
glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of
glutamate release from nerve endings by perfusion of the K(+)-channel blocker
4-aminopyridine (4-AP) in the rat hippocampus induces
seizures and neurodegeneration, and that
AMPA infusion in the spinal cord produces
paralysis and MN death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on MN survival, and the mechanisms underlying this effect. 4-AP produced muscle
fasciculations and motor deficits assessed in two motor tests, which start 2-3 h after the implant, which ameliorated spontaneously within 6-7 days, but no neurodegeneration. These effects were prevented by both
AMPA and
NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of
bicuculline induced moderate MN degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist
muscimol also induced motor deficits and failed to prevent the MN death induced by
AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to
ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces MN death under
chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of MN excitability in the spinal cord.