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Different receptors mediate motor neuron death induced by short and long exposures to excitotoxicity
L Van Den Bosch1, W Robberecht
1Laboratory of Neurobiology, Department of Neurology, University of Leuven, Leuven, Belgium. Ludo.Vandenbosch@med.kuleuven.ac.be
Abstract:
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.
Insights
Short glutamate exposures kill motor neurons via NMDA receptors. Kainate (KA) excitotoxicity involves different AMPA receptor types depending on exposure duration, with Ca(2+)-permeable AMPA receptors mediating selective motor neuron vulnerability.
Area of Science:
- Neuroscience
- Neurotoxicology
Background:
- Excitotoxicity, a process involving overstimulation of neurons, contributes to neuronal damage in various neurological conditions.
- Motor neurons are particularly vulnerable to excitotoxic insults, but the specific receptor mechanisms underlying this vulnerability are not fully understood.
Purpose of the Study:
- To compare the effects of short and long exposures to glutamate and kainate (KA) on cultured motor neurons.
- To elucidate the specific receptor subtypes involved in excitotoxicity mediated by different exposure durations and agonists.
Main Methods:
- Cultured motor neurons were exposed to varying durations of glutamate and kainate (KA).
- The roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors were investigated.
- The effect of Joro spider toxin and histochemical Co(2+) staining were used to identify Ca(2+)-permeable AMPA receptors.
Main Results:
- Both short and long glutamate exposures primarily induced motor neuron death via NMDA receptor activation.
- Preventing AMPA receptor desensitization increased motor neuron sensitivity to excitotoxicity.
- Short kainate (KA) exposures selectively killed motor neurons with Ca(2+)-permeable AMPA receptors, while long exposures affected neurons with both Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors.
Conclusions:
- Motor neuron death from glutamate excitotoxicity is mediated by NMDA receptors regardless of exposure duration.
- The type of AMPA receptor involved in kainate (KA)-induced excitotoxicity differs between short and long exposures.
- The presence of Ca(2+)-permeable AMPA receptors contributes to the selective vulnerability of motor neurons to excitotoxicity.