"Aging affects the brain in many ways, most notably by impairing memory function. On a cellular level, aging causes changes in synaptic plasticity and downregulation of energy metabolism. As our understanding of the importance of astrocytes in brain is increasing, it is clear that the knowledge on how aging affects astrocytes is lacking. The aim is, therefore, to elucidate the role of astrocytes in aging and how homeostasis of the neurotransmitter glutamate and energy metabolism alters with age and how this correlates to cognitive decline. The approach is to investigate astrocyte uptake of glutamate and energy metabolism in hippocampal slices from neonatal, adult and aged mice. Initially the effects of aging on astrocyte glutamate uptake will be quantified by measuring synaptically evoked glutamate transporter currents. Alterations in metabolic pathways will be evaluated by 13C metabolic mapping employing mass spectrometry and NMR spectroscopy. Besides being an excitatory neurotransmitter, glutamate is a substrate for energy production via conversion to a-ketoglutarate by glutamate dehydrogenase (GDH). Increased input of glutamate into the TCA-cycle may counteract a reduced energy metabolism during aging. Therefore, I will investigate the effect of GDH activity during aging, using a GDH knock out mouse and a transgenic model expressing GDH2 in addition to GDH1. To correlate the effects on uptake and metabolism to cognitive decline, I will investigate the effect of GDH activity on synaptic plasticity and spatial memory. By measuring long term potentiation in hippocampal slices and evaluating spatial memory capacity of the animals, I will be able to draw conclusions concerning the effect of altered glutamate homeostasis on cognitive decline. The project takes a grip on the issue of astrocytes in cognitive decline and aging from both the in vivo and in vitro angle. Therefore, it will contribute with new, valuable information on the role of astrocytes in the aging brain."