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Ca2+-permeable AMPA receptors and intracellular Ca2+ determine motoneuron vulnerability in rat spinal cord in vivo
Juan Carlos Corona1, Ricardo Tapia
1Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510 México, DF, Mexico.
Abstract:
Excitotoxicity mediated by overactivation of glutamate receptors, particularly the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) type, has been implicated in motoneuron degeneration. AMPA receptors lacking the GluR2 subunit are permeable to Ca(2+) and the entrance of this cation might be responsible for the selective vulnerability of spinal motoneurons in amyotrophic lateral sclerosis (ALS). To evaluate this hypothesis in vivo, we have used a model of motoneuron death in which AMPA, perfused by microdialysis in the rat lumbar spinal cord, produces ipsilateral paralysis and a remarkable loss of spinal motoneurons. Perfusion of 1-naphthyl acetyl spermine, a selective blocker of the Ca(2+)-permeable AMPA receptors, and of the intracellular Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), prevented the AMPA-induced paralysis and reduced by about 50% the loss of motoneurons. In addition, perfusion of pyruvate, an energy metabolic substrate, similarly prevented the paralysis and the motoneuron death. These results suggest that functional AMPA receptors lacking the GluR2 subunit are present in the rat spinal cord, and that motoneuron death is triggered by an increase of intracellular Ca(2+) via such Ca(2+)-permeable AMPA receptors. Our finding that pyruvate also protected against the excitotoxic effects of AMPA suggests that the increased intracellular Ca(2+) probably interferes with the mitochondrial energetic metabolism.
Insights
Calcium-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Blocking these receptors or providing pyruvate protected spinal motoneurons in a rat model.
Area of Science:
- Neuroscience
- Neurobiology
- Molecular Biology
Background:
- Excitotoxicity, driven by glutamate receptor overactivation, is linked to motoneuron degeneration.
- Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors lacking the GluR2 subunit allow calcium (Ca2+) influx, potentially causing spinal motoneuron vulnerability in amyotrophic lateral sclerosis (ALS).
Purpose of the Study:
- To investigate the role of Ca2+-permeable AMPA receptors in motoneuron death in vivo.
- To evaluate the neuroprotective effects of blocking these receptors and enhancing cellular metabolism.
Main Methods:
- A rat model of motoneuron death was established by perfusing AMPA in the lumbar spinal cord.
- Neuroprotection was assessed using a selective Ca2+-permeable AMPA receptor blocker (1-naphthyl acetyl spermine) and an intracellular Ca2+ chelator (BAPTA-AM).
- The effect of pyruvate, an energy metabolic substrate, on AMPA-induced neurotoxicity was also examined.
Main Results:
- AMPA perfusion induced paralysis and significant motoneuron loss.
- 1-naphthyl acetyl spermine and BAPTA-AM administration prevented paralysis and reduced motoneuron loss by approximately 50%.
- Pyruvate perfusion also effectively prevented paralysis and motoneuron death.
Conclusions:
- Functional Ca2+-permeable AMPA receptors are present in the rat spinal cord.
- Motoneuron death is triggered by intracellular Ca2+ increase through these receptors, likely impairing mitochondrial energy metabolism.
- Pyruvate shows neuroprotective potential against excitotoxicity by potentially supporting mitochondrial function.
