title: Manganese exposure is cytotoxic and alters dopaminergic and GABAergic neurons within the basal ganglia.
abstract: Manganese is an essential nutrient, integral to proper metabolism of amino acids, proteins and lipids. Excessive environmental exposure to manganese can produce extrapyramidal symptoms similar to those observed in Parkinson's disease (PD). We used in vivo and in vitro models to examine cellular and circuitry alterations induced by manganese exposure. Primary mesencephalic cultures were treated with 10-800 microM manganese chloride which resulted in dramatic changes in the neuronal cytoskeleton even at subtoxic concentrations. Using cultures from mice with red fluorescent protein driven by the tyrosine hydroxylase (TH) promoter, we found that dopaminergic neurons were more susceptible to manganese toxicity. To understand the vulnerability of dopaminergic cells to chronic manganese exposure, mice were given i.p. injections of MnCl(2) for 30 days. We observed a 20% reduction in TH-positive neurons in the substantia nigra pars compacta (SNpc) following manganese treatment. Quantification of Nissl bodies revealed a widespread reduction in SNpc cell numbers. Other areas of the basal ganglia were also altered by manganese as evidenced by the loss of glutamic acid decarboxylase 67 in the striatum. These studies suggest that acute manganese exposure induces cytoskeletal dysfunction prior to degeneration and that chronic manganese exposure results in neurochemical dysfunction with overlapping features to PD.
authors.affiliation: Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37620, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Stanwood
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Leitch
authors.forename: Valentina
authors.initials: V
authors.lastname: Savchenko
authors.forename: Jane
authors.initials: J
authors.lastname: Wu
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Fitsanakis
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Stankowski
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.forename: BethAnn
authors.initials: B
authors.lastname: McLaughlin
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005968:Glutamate Decarboxylase / Q000187:drug effects / Q000378:metabolism; D015636:Magnesium Chloride / Q000633:toxicity; D008345:Manganese / Q000633:toxicity*; D020149:Manganese Poisoning / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D009498:Neurotoxins; D015636:Magnesium Chloride; D008345:Manganese; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D004298:Dopamine