Exposure to an environmental neurotoxicant hastens the onset of amyotrophic lateral sclerosis-like phenotype in human Cu2+/Zn2+ superoxide dismutase 1 G93A mice: glutamate-mediated excitotoxicity.

Mice expressing the human Cu2+/Zn2+ superoxide dismutase 1 (hSOD1) gene mutation (hSOD1(G93A); G93A) were exposed to methylmercury (MeHg) at concentrations that did not cause overt motor dysfunction. We hypothesized that low concentrations of MeHg could hasten development of the amyotrophic lateral sclerosis (ALS)-like phenotype in G93A mice. MeHg (1 or 3 ppm/day in drinking water) concentration-dependently accelerated the onset of rotarod failure in G93A, but not wild-type, mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence (free intracellular calcium concentration [Ca2+](i)) in soma of brainstemhypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbar-onset ALS. The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)/kainic acid receptor antagonist 6-cyano-7nitroquinoxaline- 2,3-dione reduced [Ca2+](i) in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antag-onizes Ca2+ -permeable AMPA receptors, further reduced [Ca2+] i more effectively in MeHg-treated than untreated G93A mice, suggesting that MeHg-treated mice have a greater Ca2+-permeable AMPA receptor contribution. The non-Ca2+ divalent cation chelator N, N, N', N' -tetrakis(pyridylmethyl) ethylenediamine reduced Fluo-4 fluorescence in all G93A mice; FluoZin-(Zn2+ indicator) fluorescence was increased in all MeHg-treated mice. Thus in G93A mice Zn2+ apparently contributed measurably to the MeHginduced effect. This is the initial demonstration of accelerated onset of ALS-like phenotype in a genetically susceptible organism by exposure to low concentrations of an environmental neurotoxicant. Increased [Ca2+](i) induced by the G93A-MeHg interaction apparently was associated with Ca2+ -permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca2+](i), leading to excitotoxic cell death.