Regulation of Brain Neurotransmitter Synthesis

脑神经递质合成的调节

• 批准号: 6949628
• 负责人: SUSAN M HUTSON
• 金额: $ 38.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-05 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949628
• 关键词: Muller' s cell; aminoacid metabolism; aspartate; brain metabolism; branched chain aminoacid; enzyme activity; gabapentin; gamma aminobutyrate; gene expression; glia; glutamates; glutamine; immunocytochemistry; isozymes; laboratory rat; malates; neuroanatomy; neurotransmitter metabolism; neurotransmitter transport; nicotinamide adenine dinucleotide; nitrogen; oxidation; protein localization; pyruvate carboxylase; transaminases

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本提案的总体目标是了解调节谷氨酸代谢的机制及其与中枢神经系统（CNS）中谷氨酸神经传递的相互关系。谷氨酸和天冬氨酸是哺乳动物大脑中主要的兴奋性神经递质。这些氨基酸是不寻常的，因为它们有双重作用，首先是神经递质，其次是氮和能量代谢的重要中间体。它们在外周组织中的代谢作用已被广泛认识，但它们的代谢与脑内神经递质功能之间的关系却很少受到关注。神经传递过程中谷氨酸的释放会导致神经元中谷氨酸的丢失。如果留在突触空间，谷氨酸是兴奋毒性的。在该提案中，我们将确定改变星形胶质细胞和神经元的复杂代谢过程的影响，这些代谢过程用于解毒和补充释放的谷氨酸。我们的目标是确定支链氨基酸（BCAA）氮和支链氨基转移的贡献。e （SCAT）同工酶参与谷氨酸的合成。我们将在体外海马切片中测试通过特异性BCAT同工酶阻断BCAAs氮转移的神经学后果，并在体内降低BCAT同工酶在大鼠脑中的表达。我们还将测试神经活性药物加巴喷丁作用机制的代谢假说。我们将研究抑制由丙酮酸羧化酶（PC）催化的谷氨酸/丙酮酸循环的碳调节步骤的神经学后果。我们将确定降低PC表达对海马新生谷氨酸合成和神经传递的影响。我们将检验生酮饮食治疗顽固性癫痫的有效性是由于PC降低丙酮酸羧化的假设。我们将在体内测试利用核磁共振波谱法计算PC通路通量的代谢理论。我们最近的研究揭示了Magistretti假说的分子基础和视网膜胶质细胞中有氧糖酵解的高速率。我们将确定这一观察结果是否提供了一种将谷氨酸神经传递与谷氨酸丙酮酸循环的回旋分支联系起来的机制。这项研究的结果将为当前癫痫饮食治疗的机制提供见解，并为影响这些途径的先天性代谢错误（枫糖浆尿病和丙酮酸羧化酶缺乏症）的神经系统后果的生化基础提供见解，从而可能导致更好的治疗方案。