The effect of manganese neurotoxicity on the Gamma-Aminobutyric acid (GABA) neurotransmitter system

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Steven C. Fordahl (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Keith Erikson

Abstract: Manganese (Mn) is an essential metal that functions primarily as a cofactor for metalloenzymes contributing to numerous metabolic pathways. Exposure to excess environmental Mn overwhelms endogenous regulation, and deleterious effects disrupt neurotransmitter systems of the basal ganglia. The following studies examined the effects of Mn on (gamma)-aminobutyric acid (GABA) using in vivo microdialysis, metabolomic analysis, and primary astrocyte cell culture. Microdialysis experiments in Sprague-Dawley rats revealed that 6-week exposure to Mn (1g Mn/L drinking water) significantly elevated extracellular GABA compared to controls. Using nipecotic acid to antagonize GABA transport proteins (GATs), we identified that Mn disrupted GABA homeostasis by inhibiting GAT mediated GABA clearance. Concurrently, metabolomic analysis of Mn exposed rats uncovered drastically altered lipid metabolism highlighted by a 12- and 15-fold increase in oleic and palmitic acids compared to control, respectively. Brain Mn accumulation was accompanied by abnormal stereotypy and was significantly correlated with plasma homogentisic, chenodeoxycholic, and aspartic acids, identifying biomarkers that correspond with Mn neurotoxicity. To elucidate mechanisms driving Mn induced changes in GABA uptake, primary astrocytes were exposed to Mn with or without oleic or palmitic acid. 3H-GABA uptake was significantly reduced by Mn and exacerbated by oleic or palmitic acids. Plasma membrane levels of GAT3 were unaltered by Mn or fatty acids despite increased regulatory protein kinase C (PKC) phosphorylation; however, fatty acid treatments augmented Mn accumulation at the plasma membrane of astrocytes. Moreover, control cells exposed to Mn exclusively during the experimental uptake had significantly reduced 3H-GABA uptake, and the addition of 50 µM GABA blunted cytosolic Mn accumulation. These data indicate that reduced GAT3 function in astrocytes is not driven by PKC signaling, but is likely influenced by Mn and fatty acids interacting with the plasma membrane, thereby inhibiting GABA uptake via GAT3. Together these studies improve our understanding of how Mn alters GABA neurotransmission upon overexposure. Furthermore, these data provide candidate biomarkers to improve early detection of Mn intoxication prior to irreparable damage.

Additional Information

Language: English
Date: 2013
Astrocyte, GABA, Manganese, Metabolomics, Neurotoxicity
Manganese $x Toxicology
Manganese $x Physiological effect
Manganese $x Metabolism
GABA $x Physiological effect
GABA $x Metabolism

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