Mice expressing the human SOD1 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 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 wt mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence ([Ca2+]i), in soma of brainstem-hypoglossal nucleus. These motoneurons control intrinsic and some extrinsic tongue function, and exhibit vulnerability in bulbar-onset ALS. The AMPA receptor antagonist CNQX 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 was apparently 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.
- Calcium-permeable AMPA receptors
- glutamate release
- intracellular calcium
- motor neuron physiology
- mouse model
- Received September 15, 2010.
- Revision received May 5, 2011.
- Accepted May 9, 2011.
- The American Society for Pharmacology and Experimental Therapeutics