The overall goal of this proposal is to understand mechanisms that regulate glutamate metabolism and how it interrelates with glutamate neurotransmission in the central nervous system (CNS). Glutamate and aspartate are the major excitatory neurotransmitters in the mammalian brain. These amino acids are unusual, because they have dual roles, first as neurotransmitters, and second as important intermediates in nitrogen and energy metabolism. Their metabolic roles in peripheral tissues are well recognized, but the relationship between their metabolism and neurotransmitter function in the brain has received much less attention. Release of glutamate during neurotransmission generates a loss of glutamate from the neuron. If left in the synaptic space, the glutamate is excitotoxic. In the proposal we will determine the effect of altering the complex metabolic processes in astroglia and neurons that operate to detoxify and replenish the released glutamate. Our goal is to define the contribution of branched chain amino acid (BCAA) nitrogen and the branched chain aminotransferas.e (SCAT) isozymes to the synthesis of glutamate. We will test the neurological consequences of blocking nitrogen transfer from BCAAs via specific BCAT isozymes in vitro in hippocampal slices and after lowering expression of BCAT isozymes in vivo in rat brain. We will also test the metabolic hypothesis for the mechanism of action of neuroactive drug gabapentin. We will examine neurological consequences of inhibiting the carbon regulatory step of the glutamate/pyruvate cycle catalyzed by pyruvate carboxylase (PC). We will determine the consequences of lowering PC expression on de novo glutamate synthesis and neurotransmission in hippocampus. We will test the hypothesis that the efficacy of the ketogenic diet in treating intractable epilepsy results from lowering pyruvate carboxylation by PC. We will test, in vivo, the metabolic theory underlying current models for calculating flux through PC pathway using nuclear magnetic resonance spectroscopy. Our recent studies reveal the molecular basis for the Magistretti hypothesis and the high rates of aerobic glycolysis in retinal glia. We will determine if this observation provides a mechanism for tying glutamate neurotransmission to the anaplerotic arm of the glutamate pyruvate cycle Results from this study will provide insight into mechanisms underling current dietary treatments for epilepsy and insight into the biochemical basis of the neurological consequences of inborn errors of metabolism that affect these pathways (Maple Syrup Urine Disease and Pyruvate Carboxylase deficiency) that may lead to better treatment regimens. ? ? ?
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