Different receptors mediate motor neuron death induced by short and long exposures to excitotoxicity

We compared the effect of short and long exposures of cultured motor neurons to glutamate and kainate (KA) and studied the receptors involved in these two types of excitotoxicity. There was no difference in the receptor type used between short and long glutamate exposures as activation of the N-methyl-D-asparate (NMDA) receptor was in both cases responsible for the motor neuron death. Cell death through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors only became apparent when desensitization of these receptors was prevented. In such conditions, motor neurons became much more sensitive to excitotoxicity, and activation of different types of AMPA receptors mediated motor neuron death after short, compared to long, exposures to the non-desensitizing AMPA receptor agonist, KA. Short KA exposures selectively affected motor neurons containing Ca(2+)-permeable AMPA receptors, as the KA effect was completely inhibited by Joro spider toxin and only motor neurons that were positive for the histochemical Co(2+) staining were killed. A long exposure to KA affected motor neurons through both Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The selective death of motor neurons vs. dorsal horn neurons was observed after short KA exposures indicating that the selective vulnerability of motor neurons to excitotoxicity is related to the presence of Ca(2+)-permeable AMPA receptors.