| 15885796 |
Raiteri L, Zappettini S, Stigliani S, Paluzzi S, Raiteri M, Bonanno G: Glutamate release induced by activation of glycine and GABA transporters in spinal cord is enhanced in a mouse model of amyotrophic lateral sclerosis. Neurotoxicology. 2005 Oct;26(5):883-92.
Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease, involving both upper and lower motor neurons, the cause of which is obscure, although glutamate (GLU)-induced excitotoxicity has been suggested to play a major role. We studied the release of [3H] d-aspartate ([3H] d-ASP) and endogenous glutamate evoked by glycine (GLY) or GABA from spinal cord synaptosomes in mice expressing a mutant form of human SOD1 with a Gly93Ala substitution ([SOD1-G93A (+)]), a transgenic model of amyotrophic lateral sclerosis, in mice expressing the non-mutated form of human SOD1 [SOD1+], and in non-transgenic littermates [SOD1 (-)/G93A (-)]. In parallel experiments, we also studied the release of [3H] GABA evoked by GLY and that of [3H] GLY evoked by GABA. Mutant mice were killed at advanced phase of pathology or during the pre-symptomatic period. In SOD1 (-)/G93A (-) or SOD1 (+) mice GLY evoked [3H] d-ASP and [3H] GABA release, while GABA caused [3H] d-ASP, but not [3H] GLY, release. The GLY-evoked release of [3H] d-ASP, but not that of [3H] GABA, and the GABA-evoked [3H] d-ASP release, but not that of [3H] GLY, were more pronounced in SOD1-G93A (+) than in SOD1 (+) or SOD1 (-)/G93A (-) mice. Furthermore, the excessive potentiation of [3H] d-ASP by GLY or GABA was already present in asymptomatic 30-40 day-old SOD1-G93A (+) mice. The releases of endogenous glutamate and GABA also were enhanced by GLY and the GLY-evoked release of endogenous glutamate, but not of endogenous GABA, was higher in SOD1-G93A (+) than in control animals. Potentiation of the spontaneous amino acid release is likely to be mediated by activation of a GLY or a GABA transporter, since the effect of GLY was counteracted by the GLY transporter blocker glycyldodecylamide but not by the GLY receptor antagonists strychnine and 5,7-dichlorokynurenate while the effect of GABA was diminished by the GABA transporter blocker SKF89976-A but not by the GABA receptor antagonists SR9531 and CGP52432. It is concluded that the glutamate release machinery seems excessively functional in SOD1-G93A (+) animals. |
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