Cerebral neurons of transgenic ALS mice are vulnerable to glutamate release stimulation but not to increased extracellular glutamate due to transport blockade.
Mechanisms of motor neuron loss in amyotrophic lateral sclerosis (ALS) are unknown, but it has been postulated that excitotoxicity due to excessive glutamatergic neurotransmission by decreased efficiency of glutamate transport may be involved in both familial (FALS) and sporadic ALS. Using microdialysis in vivo, we tested the effects of the glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC) and of 4-aminopyridine (4-AP), which stimulates glutamate release from nerve endings, in the hippocampus and motor cortex of wild type (WT) and transgenic SOD1/G93A mice, an established model of FALS. Perfusion of 4-AP induced convulsions, expression of the inducible stress-marker heat-shock protein 70 (HSP70) and hippocampal neuronal loss. These effects were similar in both WT and G93A mice, and, in both groups, they were prevented by the previous systemic administration of the NMDA receptor antagonist MK-801. In contrast, perfusion of PDC resulted in a large and long-lasting (2 h) increase of extracellular glutamate, but no convulsions, neuronal damage or HSP70 expression were observed in either the WT or the G93A mice. Our results demonstrate that SOD1 G93A mutation does not enhance the vulnerability to endogenous glutamate-mediated excitotoxicity in brain, neither by blocking glutamate transport nor by stimulating its release. Therefore, these data do not support the possibility that glutamate transport deficiency may be an important factor of brain neuronal degeneration in familial ALS.
Tovar-y-Romo
Luis B
LB
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510-México, D. F., México.
Tapia
Ricardo
R
D015761:4-Aminopyridine / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics
D003998:Dicarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D050884:HSP72 Heat-Shock Proteins; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C083486:pyrrolidine-2,4-dicarboxylic acid; D015761:4-Aminopyridine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase