dc.description.abstract | Glutamate has been shown to lead to neurotoxicity and subsequent neurodegeneration through changes in synaptic function, loss of glutamatergic neurons, synapses, and dendrites. All of these characteristics are also observed during aging or in age-associated neurodegenerative diseases. To probe the effects of excess glutamate and determine if these effects might contribute to the morphological and functional changes associated with aging, our laboratory generated a transgenic mouse model that over-expresses the mitochondrial glutamate dehydrogenase 1 (GLUD1) gene. This transgene was only expressed in neurons through the use of the neuron-specific enolase promoter. The Glud1 Tg mouse model generated in our laboratory demonstrated significantly increased GLUD1 levels, GLUD activity, extracellular glutamate levels, and increased glutamate release after stimulation as compared to wild type (wt). There were also many significant morphological changes observed in the Tg mice including cell layer thinning in the hippocampus, cortex, and striatum, accompanied by synapse, neuronal, and dendrite losses. It was noted that the morphological changes observed were within specific brain regions; for example, the cerebellum showed no changes despite the fact that Glud1 was over-expressed in all neuronal cells. In addition, the morphological changes in the various brain regions of the Tg mice were further exacerbated by advancing age. Selective neuronal vulnerability has also been observed in many neurodegenerative diseases and has been found to occur in the cerebral cortex, hippocampus, and amygdala neurons of those with Alzheimer's disease. Therefore, the Glud1 Tg mice may be used to probe the molecular and cellular pathways involved in selective neuronal vulnerability as it may relate to excess extracellular glutamate. The studies presented in this dissertation focused on investigating the role of mitochondria in inducing region specific neuronal degeneration under the conditions of the combined effects of aging and excess glutamate activity in the central nervous system. Specifically, I have focused on whether there are changes in mitochondrial bioenergetics (Chapter 2), mitochondrial Ca2+ regulation (Chapter 3), and mitochondrial reactive oxygen species generation (Chapter 4) during the aging process in different brain regions in wild type and Glud1 Tg mice. Our studies demonstrated that there are altered mitochondrial electron transport system activities, mitochondrial calcium dishomeostasis, mitochondrial membrane potential, and generation of reactive oxygen species in the Tg as compared to wt mice. Complex I of the electron transport system is significantly lower in the Tg as compared to wt mice at 9 months in the cerebellum. In addition, the membrane potential in the Tg mice as compared to wt mice is 2-fold higher and the same results were demonstrated for the levels of superoxide. Mitochondrial calcium uptake in the Tg mice is 2-fold higher than wt mice at 9 months and significantly decreases across advances age. Taken together, these data suggest some adaptive and compensatory mechanisms might be taken place in the Tg mice as a result of the over-expression of the Glud1 gene i.e. down-regulated complex I activity and decreased calcium uptake across age. | |