"Methylmercury (MeHg) can affect both the peripheral and central nervous system; however, granule cells in the cerebellum are preferential targets of MeHg neurotoxicity. The loss of granule cell after MeHg exposure is believed to be the result of unregulated elevations in intracellular calcium concentrations ([Ca2+]i) that lead to glutamate excitotoxicity. Astrocytes are the main cell type responsible for buffering the excess extracellular glutamate levels, preventing the excitotoxicity of neurons. However, MeHg can also affect astrocytes and increase their [Ca2+]i. MeHg-induced cytotoxicity in astrocytes has been studied in the forebrain cortex. However, effects on cerebellar astrocytes are less studied. Because regional differences can occur in astrocytes between the two areas, in this dissertation we compared MeHg toxicity on cerebellar and cortical astrocytes, and aimed to understand different toxicological effects of MeHg on these astrocytes, such as, the increase in extracellular glutamate levels and cytotoxicity. After an acute exposure to MeHg, there was a regional, but not a typological difference in astrocyte viability, in where cerebellar astrocytes were more susceptible to MeHg than cortical astrocytes. One difference between cortical and cerebellar astrocytes that might contribute to the cerebellar astrocytes susceptibility to MeHg was the contribution of calcium (Ca2+) to cell death. It was found that intracellular Ca2+ plays a role in MeHg-induced cortical astrocyte death. However, both intracellular and extracellular Ca2+ contribute to cerebellar astrocyte death. Another factor that contributes to the regional susceptibility of cerebellar astrocytes to MeHg was the Ca2+-dependent vesicular release of glutamate. These releases occurred in cerebellar astrocytes and not in cortical astrocytes, and were not due to the smooth endoplasmic reticulum (SER), but to the interaction of MeHg with the mitochondria, L-type and N-type voltage-gated Ca2+ channels (VGCCs). However, there were no differences in the contribution of these intracellular storages and Ca2+ channels to the reduction of viability. MeHg can also affect the excitatory amino acid transporters (EAATs), inducing an upregulation and dysfunction of these proteins. By studying the effect of MeHg on astrocytes, we found that the Ca2+-dependent vesicular release of glutamate from cerebellar astrocytes and the dysfunction of the EAATs contribute to cerebellar astrocyte susceptibility. The noticeable effects of MeHg exposure in glutamate levels observed on cerebellar astrocytes might contribute to the preferential sensitivity of the granule cells to MeHg by further increasing neuronal excitotoxicity."-Pages ii-iii.
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