RT Journal Article
SR Electronic
T1 Exposure to an Environmental Neurotoxicant Hastens the Onset of Amyotrophic Lateral Sclerosis-Like Phenotype in Human Cu<sup>2+</sup>/Zn<sup>2+</sup> Superoxide Dismutase 1 G93A Mice: Glutamate-Mediated Excitotoxicity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 518
OP 527
DO 10.1124/jpet.110.174466
VO 338
IS 2
A1 Frank O. Johnson
A1 Yukun Yuan
A1 Ravindra K. Hajela
A1 Alisha Chitrakar
A1 Dawn M. Parsell
A1 William D. Atchison
YR 2011
UL http://jpet.aspetjournals.org/content/338/2/518.abstract
AB Mice expressing the human Cu2+/Zn2+ superoxide dismutase 1 (hSOD1) gene mutation (hSOD1G93A; 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 brainstem-hypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbar-onset ALS. The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione reduced [Ca2+]i in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antagonizes 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 MeHg-induced 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.