Methymercury (MeHg) is an environmental neurotoxicant of current concern. It bioaccumulates in humans, via consumption of contaminated fish, causing deficiencies in motor function. The mechanism(s) underlying the MeHg-induced neuronal injury are not yet understood, but nerve cells die. Due to the prevalence of MeHg in the environment, superimposed with the high incidence for sporadic Amyotrophic Lateral Sclerosis (Guallar et al.), gene and environmental interactions have been proposed. At the Renshaw area, excitatory motor neurons (MNs) and inhibitory Renshaw cells (RCs) participate in a negative-feedback mechanism that control hindlimb muscles. Disruption of recurrent inhibition by too much excitation or too low inhibition disrupts this circuit towards a state of hyperexcitability. MeHg affects both excitatory and inhibitory neurotransmission, being the later the most sensitive. Also, MeHg-induced cell death is associated to increases in intracellular calcium (Ca2+) concentration ([Ca2+]i). In detail, MeHg triggers Ca2+ efflux from intracellular Ca2+ stores followed by Ca2+ influx from the extracellular solution. Cholinergic receptors participate of MeHg-mediated alterations of Ca2+i homeostasis in CGCs. The purpose of this research is to determine whether known targets of MeHg neurotoxicity contribute to dysfunction in cells that degenerate in ALS. Specifically, to examine the role of the nicotinic acetylcholine receptor (nAChR), [gamma]-aminobutyric acid type A receptor (GABAAR), glycine receptor (GlyR), and intracellular Ca2+ stores to the acute effects of MeHg neurotoxicity. The heteropentameric nAChR contributes to MeHg (in vitro)-induced increase in [Ca2+]i and subsequent cell death. Furthermore, this occurred in an extracellular Ca2+-dependent fashion. The nAChR and GABAAR, but not GlyR, contributes to the MeHg (in situ)-induced increase in [Ca2+]i. Intracellular Ca2+ pools also participate of the MeHg-mediated increase in [Ca2+]i. However, only the GABAAR is involved during MeHg-induced cell death in the Renshaw area. This research contributes to our understanding the effects of metal-induced neuronal injury in a group of cells that degenerate during ALS.
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