Title: 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.

Authors: Johnson, Frank O; Yuan, Yukun; Hajela, Ravindra K; Chitrakar, Alisha; Parsell, Dawn M; Atchison, William D

Published In J Pharmacol Exp Ther, (2011 Aug)

Abstract: Mice expressing the human Cu(2+)/Zn(2+) 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 [Ca(2+)](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 [Ca(2+)](i) in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antagonizes Ca(2+)-permeable AMPA receptors, further reduced [Ca(2+)](i) more effectively in MeHg-treated than untreated G93A mice, suggesting that MeHg-treated mice have a greater Ca(2+)-permeable AMPA receptor contribution. The non-Ca(2+) divalent cation chelator N,N,N',N'-tetrakis(pyridylmethyl)ethylenediamine reduced Fluo-4 fluorescence in all G93A mice; FluoZin-(Zn(2+) indicator) fluorescence was increased in all MeHg-treated mice. Thus in G93A mice Zn(2+) 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 [Ca(2+)](i) induced by the G93A-MeHg interaction apparently was associated with Ca(2+)-permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca(2+)](i), leading to excitotoxic cell death.

PubMed ID: 21586603

MeSH Terms: No MeSH terms associated with this publication