Is chemical neurotransmission altered specifically during methylmercury-induced cerebellar dysfunction?
Methylmercury (MeHg) is an important environmental neurotoxicant that is present in seafood and affects the developing and mature nervous system. The neurotoxicity induced by MeHg is a concern, particularly for fish-eating populations and pregnant or nursing women. During MeHg-induced neurotoxicity, degeneration of the granule cell layer in the cerebellum occurs, which leads to deficits in motor function. I suggest that the action of MeHg on specific neurotransmitter receptors contributes to the selective vulnerability of granule cells. MeHg appears to stimulate M(3) muscarinic acetylcholine receptors and to inhibit GABA(A) receptor subtypes preferentially on cerebellar granule cells. This could lead to the loss of tonic inhibition of granule cells as a result of antagonism of GABA(A) receptors, and a M(3)-receptor-mediated increase in the intracellular concentration of Ca(2+) and block of a K(+)-dependent leak current. The net result would be increased spontaneous release of glutamate, which, coupled with a MeHg-induced impairment of glutamate uptake by astrocytes, could cause Ca(2+)-mediated cytotoxicity.
Atchison
William D
WD
Department of Pharmacology & Toxicology, Michigan State University, B-331 Life Sciences Building, East Lansing, MI 48824-1317, USA. atchiso1@msu.edu
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004785:Environmental Pollutants / Q000633:toxicity*; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000633:toxicity*; D011689:Purkinje Cells / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000819:agonists* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D004785:Environmental Pollutants; D058787:GABA-A Receptor Antagonists; D008767:Methylmercury Compounds; D018377:Neurotransmitter Agents; D043587:Receptor, Muscarinic M3; D011963:Receptors, GABA-A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium