A variety of metabolic imaging studies, including FDG PET and MRS, have suggested metabolic and energy deficiencies in epileptogenic regions of certain symptomatic epilepsies. In particular, the 1H NMR measurements of N-acetyl aspartate (NAA) may indicate mitochondrial dysfunction and the 31P NMR demonstrates depleted high energy phosphates. The medial temporal lobe epilepsy (MTLE) patients have been the most frequently studied and localized by these methods. Hippocampal tissue removed from these patients to control medically intractable seizures has revealed cytochrome c oxidase (COX) and Na/k ATPase dysregulation also suggesting that the metabolic imaging studies may be detecting mitochondrial dysfunction or loss. In vivo hippocampal microdialysis studies have implicated glutamate transporter malfunction as a significant function link tying a low energy state to poor glutamate clearance and excess excitation. Thus, the hypothesis of this grant states that energy compromise may exist in MTLE triggering an excitatory cascade with inadequate glutamate metabolism and altered neuronal-glial neurotransmitter cycling and subsequent poor extracellular glutamate clearance leading to the spread of excitability. Project 1 will initially address this hypothesis by examining CMR glucose with FDG PET, high energy phosphates (PCr and ATP) with 31 PNMR and a neuronal dysfunction with 1H NMR of NAA. These measurements of tricarboxylic acid (TCA) 13C and anaplerotic rates of glutamate cycling and glutamine synthesis will be addressed in vivo with controls and correlated with in vitro 13C cycling rates in the resected tissue described in Project 2. Project 3 will correlate these findings with human tissue mitochondrial dysfunction, density, hyperplasia and DNA analysis along with COX and glutamate transporters. Finally, the functional consequences of this hypothesis will be tested in Project 4 examining the ECF space, k+ and glutamate regulation in the human and control kainate rat model.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1-SRB-W (01))
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Fureman, Brandy E
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Yale University
Schools of Medicine
New Haven
United States
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