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Dysregulation of Glutamate Cycling Mediates Methylmercury-Induced Neurotoxicity

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The Glutamate/GABA-Glutamine Cycle

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 13))

Abstract

To examine the toxicological implications of glutamate, this chapter will focus specifically on its impact in the brain. More explicitly, it will illustrate the role glutamate plays in mediating methylmercury (MeHg)-induced neurotoxicity. In this chapter, one intends to highlight the processes that occur prior to glutamate-stimulated excitotoxicity and subsequent neurodegeneration. As such, it will emphasize three main routes by which MeHg alters glutamate homeostasis. It is essential to recognize that these effects are not mutually exclusive, and that they synergistically influence glutamate dysregulation. Furthermore, the consequences of MeHg exposure will be presented here as a direct pathway; however, it must be noted these effects occur simultaneously. First, glutamate uptake will be reviewed emphasizing the function of astrocytes. Next, the induction of oxidative stress by MeHg exposure will be discussed. This process has a two-fold effect on glutamate homeostasis by (1) inhibiting extracellular glutamate uptake and (2) altering transcription of genes vital to glutamate cycling. Finally, the impact glutamate dysregulation has on glutathione synthesis will be examined. Although this chapter centers on the link between glutamate and MeHg toxicity, it is imperative that the reader acknowledges the processes discussed here can be extended to any pro-oxidant.

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Acknowledgments

The review was supported in part by NIH grants from the National Institute of Environmental Health Sciences ES R01 07331 and R01 ES 020852.

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Megan Culbreth & Michael Aschner

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  1. Megan Culbreth
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  2. Michael Aschner
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Correspondence to Megan Culbreth .

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Editors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Arne Schousboe

  2. Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    Ursula Sonnewald

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Culbreth, M., Aschner, M. (2016). Dysregulation of Glutamate Cycling Mediates Methylmercury-Induced Neurotoxicity. In: Schousboe, A., Sonnewald, U. (eds) The Glutamate/GABA-Glutamine Cycle. Advances in Neurobiology, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-45096-4_11

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