The Glutamate/GABA-Glutamine Cycle

Megan Culbreth, Michael Aschner, Culbreth, Megan, Aschner, Michael

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.