AMPA receptor contribution to methylmercury-mediated alteration of intracellular Ca2+ concentration in human induced pluripotent stem cell motor neurons |
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| Affiliation: | 1. Department of Pharmacology and Toxicology, College of Veterinary Medicine, Michigan State University, 1355 Bogue St., B338 Life Science Bldg., East Lansing, MI 48824, United States;2. Institute for Integrative Toxicology, College of Veterinary Medicine, Michigan State University, 1355 Bogue St., B338 Life Science Bldg., East Lansing, MI 48824, United States;3. Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, 1355 Bogue St., B331 Life Science Bldg., East Lansing, MI 48824, United States;1. Ministry of Health, Mahé, Republic of Seychelles, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;2. Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;3. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;1. Strong Center for Developmental Disabilities, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;2. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;3. Ministry of Health, Republic of Seychelles;4. Ministry of Education and Culture, Republic of Seychelles;5. Department of Biostatistics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;1. School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA;2. Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA;1. Neurology Department, Hassan II University Hospital of Fez, Morocco;2. Moroccan Society of History of Medicine and Neurosciences, Morocco;3. Université de Strasbourg, 67000, Strasbourg, France;4. Association RISE, 67205, Oberhausbergen, France;5. Endocrinology Department, Montpellier-Nîmes University, France;6. Department of Neurology, School of Medicine, and Oregon Institute for Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA |
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| Abstract: | α motor neurons (MNs) are a target of the environmental neurotoxicant methylmercury (MeHg), accumulating MeHg and subsequently degenerating. In mouse spinal cord MN cultures, MeHg increased intracellular Ca2+ [Ca2+]i; the AMPA receptor (AMPAR) antagonist CNQX delayed the increase in [Ca2+]i, implicating the role of AMPARs in this response. Here we used human induced pluripotent stem cell-derived MNs (hiPSC-MNs), to characterize the role of MN AMPARs in MeHg neurotoxicity. Acute exposure to MeHg (0.1, 0.2, 0.5, 1 and 1.5 μM), fura-2 microfluorimetry, and a standard cytotoxicity assay, were used to examine MN regulation of [Ca2+]i, and cytotoxicity, respectively. Contribution of Ca2+-permeable and impermeable AMPARs was compared using either CNQX, or the Ca2+-permeable AMPAR antagonist N-acetyl spermine (NAS). MeHg-induced cytotoxicity was evaluated following a 24 h delay subsequent to 1 h exposure of hiPSC-MNs. MeHg caused a characteristic biphasic increase in [Ca2+]i, the onset of which was concentration-dependent; higher MeHg concentrations hastened onset of both phases. CNQX significantly delayed MeHg’s effect on onset time of both phases. In contrast, NAS significantly delayed only the 2nd phase increase in fura-2 fluorescence. Exposure to MeHg for 1 h followed by a 24 h recovery period caused a concentration-dependent incidence of cell death. These results demonstrate for the first time that hiPSC-derived MNs are highly sensitive to effects of MeHg on [Ca2+]i, and cytotoxicity, and that both Ca2+-permeable and impermeable AMPARs contribute the elevations in [Ca2+]i. |
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| Keywords: | Methylmercury Motor neurons Ion channel Glutamate AMPA receptor Intracellular calcium |
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