Cellular mechanisms underlying neurotoxic actions of methylmercury (MeHg) in the peripheral and central nervous system will be studied in mammals using intracellular microelectrode recording techniques and radiochemical flux determinations. The objectives are to determine: a) whether MeHG produces changes in synaptic transmission in cortical neurons which correspond to those observed in peripheral, somatic nerves; b) whether MeHg nerve Ca2+ channels, and if so whether the ionic selectivity of the channel is altered, whether the effects are preferential for a particular type of Ca2+ channel, and whether congeners of MeHg produce similar effects; c) whether MeHg blocks Ca2+ uptake or induces Ca2+ release from neuronal mitochondria and/or smooth endoplasmic reticulum; d) whether MeHg enters the nerve terminal, if so, by what path it enters, and where it goes; e) whether MeHg produces postsynaptic effects at the neuromuscular junction; f) to what extent do the electrophysiological changes described for MeHg occur when a permanently uncharged organic, or a monovalent inorganic form of Hg is used; and g) whether electrophysiological changes described with acute application of MeHg occur when animals are treated chronically with MeHg? Intracellular microelectrode recordings including voltage clamp and quantitative iontophoresis will be made from the somatic neuromuscular junction of the rat and from mossy fiber/CA3 pyramidal cell excitatory synapses in isolated hippocampal slices of the guinea pig. Effects of MeHg on nerve-evoked and spontaneous release will be measured. Effects of MeHg on Ca2+- driven action potentials in hippocampal cells will be studied. Effects of MeHg on Ca2+ currents in N1E-115 neuroblastoma cells using whole cell patch voltage clamp will be used to determine if MeHg blocks Ca2+ channels. Effects of MeHg on Ca2+ channel ion selectivity will be assessed using uptake of radiolabelled Ca, Sr and Ba. Comparative effects of structurally-related mercurials on calcium influx will also be studied. Synaptosomes will also be used to test whether MeHg enters the nerve terminal, and if so how MeHg interacts with intracellular Ca2+ regulatory systems in the nerve terminal. Measurements of nerve-evoked and spontaneous release from motor nerves of rats treated chronically with MeHg will be used to assess the relevance to chronic MeHg neurotoxicity of the changes described previously for acute intoxication. Results from the proposed studies should provide answers to questions concerning the interaction of MeHg with cortical synaptic transmission, the interaction with Ca2+ in synaptic transmission at both membrane and intracellular loci, and the effects of chronic MeHg poisoning on synaptic transmission.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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Michigan State University
Schools of Veterinary Medicine
East Lansing
United States
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Colón-Rodríguez, Alexandra; Hannon, Heidi E; Atchison, William D (2017) Effects of methylmercury on spinal cord afferents and efferents-A review. Neurotoxicology 60:308-320
Tsai, Tidao; Yuan, Yukun; Hajela, Ravindra K et al. (2017) Methylmercury induces an initial increase in GABA-evoked currents in Xenopus oocytes expressing ?1and ?6subunit-containing GABAAreceptors. Neurotoxicology 60:161-170
Bradford, Aaron B; Mancini, Jayme D; Atchison, William D (2016) Methylmercury-Dependent Increases in Fluo4 Fluorescence in Neonatal Rat Cerebellar Slices Depend on Granule Cell Migrational Stage and GABAA Receptor Modulation. J Pharmacol Exp Ther 356:2-12
Hoffman, Daniel J; Newland, M Christopher (2016) A microstructural analysis distinguishes motor and motivational influences over voluntary running in animals chronically exposed to methylmercury and nimodipine. Neurotoxicology 54:127-139
Shen, Andrew Nathanael; Cummings, Craig; Pope, Derek et al. (2016) A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection. Behav Brain Res 311:147-159
Yuan, Yukun; Atchison, William D (2016) Multiple Sources of Ca2+ Contribute to Methylmercury-Induced Increased Frequency of Spontaneous Inhibitory Synaptic Responses in Cerebellar Slices of Rat. Toxicol Sci 150:117-30
Shen, Andrew Nathanael; Pope, Derek A; Hutsell, Blake A et al. (2015) Spatial discrimination reversal and incremental repeated acquisition in adolescent and adult BALB/c mice. Behav Processes 118:59-70
Tiernan, Chelsea T; Edwin, Ethan A; Hawong, Hae-Young et al. (2015) Methylmercury impairs canonical dopamine metabolism in rat undifferentiated pheochromocytoma (PC12) cells by indirect inhibition of aldehyde dehydrogenase. Toxicol Sci 144:347-56
Newland, M Christopher; Reed, Miranda N; Rasmussen, Erin (2015) A hypothesis about how early developmental methylmercury exposure disrupts behavior in adulthood. Behav Processes 114:41-51
VanDuyn, Natalia; Nass, Richard (2014) The putative multidrug resistance protein MRP-7 inhibits methylmercury-associated animal toxicity and dopaminergic neurodegeneration in Caenorhabditis elegans. J Neurochem 128:962-74

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