Regulation of Brain Neurotransmitter Synthesis

脑神经递质合成的调节

• 批准号: 7680904
• 负责人: SUSAN M HUTSON
• 金额: $ 14.56万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680904
• 关键词: Activity Cycles; Affect; Alanine; Amino Acids; Antisense Technology; Area; Aspartate; Astrocytes; Attention; Back; Beta Catenin Staining Method; Biochemical; Brain; Branched-Chain Amino Acids; Carbon; Cells; Citric Acid Cycle; Complex; Data; Decarboxylation; Diet; Drug Metabolic Detoxication; Effectiveness; Energy Metabolism; Enzymes; Epilepsy; Equilibrium; Funding; Glucose; Glutamate Metabolism Pathway; Glutamates; Glutaminase; Glutamine; Glycolysis; Goals; Hippocampus (Brain); In Vitro; Inborn Errors of Metabolism; Infusion procedures; Intractable Epilepsy; Isoenzymes; Keto Acids; Lead; Left; Leucine; Link; Malate-Aspartate Shuttle Pathway; Malates; Maple Syrup Urine Disease; Maps; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Muller' s cell; NADH; NMR Spectroscopy; Nerve Degeneration; Neuraxis; Neuroglia; Neurologic; Neurons; Neurotransmitters; Nitrogen; Operative Surgical Procedures; Oxalacetic Acid; Oxidation-Reduction; Pathway interactions; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Physiological; Principal Investigator; Protein Isoforms; Pyruvate; Pyruvate Carboxylase; Pyruvates; Rate; Rattus; Regulation; Rest; Retina; Retinal; Role; Series; Site; Slice; Source; Spatial Distribution; Spinal Cord; Synapses; Testing; Tissues; Treatment Protocols; Upper arm; aerobic glycolysis; aspartate-glutamate carrier; awake; base; branched-chain-amino-acid transaminase; carboxylation; defined contribution; gabapentin; gamma-Aminobutyric Acid; in vivo; inhibitor/antagonist; insight; ketogenic diet; malate; neuroprotection; neurotransmission; neurotransmitter metabolism; oxidation; programs; sample fixation; theories

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）：该提案的总体目标是了解调节谷氨酸代谢的机制，以及它如何与中枢神经系统（CNS）中的谷氨酸神经传递相互关联。谷氨酸和天冬氨酸是哺乳动物大脑中的主要兴奋性神经递质。这些氨基酸是不寻常的，因为它们具有双重作用，首先是神经递质，其次是氮和能量代谢中的重要中间体。它们在周围组织中的代谢作用得到了充分认识，但是它们的代谢与大脑中神经递质功能之间的关系受到了较少的关注。神经传递期间的谷氨酸释放会导致神经元的谷氨酸损失。如果留在突触空间中，则谷氨酸是兴奋的。在该提案中，我们将确定改变星形胶质细胞和神经元中复杂的代谢过程的影响，这些过程可作用于排毒和补充释放的谷氨酸。我们的目标是定义分支链氨基酸（BCAA）氮和分支链氨基替代品的贡献，E（SCAT）同工酶对谷氨酸的合成。我们将通过特定的BCAT同工酶在海马切片中的特定BCAT同工酶和降低大鼠脑中BCAT同工酶的表达后，通过特定的BCAT同工酶在体外测试氮从BCAA的转移的神经系统后果。我们还将检验代谢假设，以实现神经活性药物加巴喷丁的作用机理。我们将检查抑制丙酮酸羧化酶（PC）催化的谷氨酸/丙酮酸周期的碳调节步骤的神经系统后果。我们将确定在海马中降低PC表达对从头谷氨酸合成和神经传递的后果。我们将检验以下假设：生酮饮食在治疗顽固性癫痫中的功效是由于PC降低丙酮酸羧化而引起的。我们将在体内测试使用核磁共振光谱通过PC途径计算通量的电流模型的代谢理论。我们最近的研究揭示了视网膜神经胶质中马格斯蒂蒂假设的分子基础和有氧糖酵解的高速率。 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缺乏）可能会导致更好的治疗方案。

项目成果

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.

I型戊二酸血症的年龄依赖性易感性机制及新治疗策略。

• DOI: 10.1172/jci31617
• 发表时间: 2007
• 期刊: The Journal of clinical investigation
• 作者: Zinnanti,WilliamJ;Lazovic,Jelena;Housman,Cathy;LaNoue,Kathryn;O'Callaghan,JamesP;Simpson,Ian;Woontner,Michael;Goodman,StephenI;Connor,JamesR;Jacobs,RussellE;Cheng,KeithC
• 通讯作者: Cheng,KeithC

Whole-brain glutamate metabolism evaluated by steady-state kinetics using a double-isotope procedure: effects of gabapentin.

使用双同位素程序通过​​稳态动力学评估全脑谷氨酸代谢：加巴喷丁的作用。

• DOI: 10.1111/j.1471-4159.2004.02576.x
• 发表时间: 2004
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Xu,Y;Oz,G;LaNoue,KF;Keiger,CJ;Berkich,DA;Gruetter,R;Hutson,SH
• 通讯作者: Hutson,SH

Expression of mitochondrial branched-chain aminotransferase and α-keto-acid dehydrogenase in rat brain: implications for neurotransmitter metabolism.

• DOI: 10.3389/fnana.2012.00018
• 发表时间: 2012
• 期刊: Frontiers in neuroanatomy
• 影响因子: 2.9
• 作者: Cole JT;Sweatt AJ;Hutson SM
• 通讯作者: Hutson SM

Branched-chain amino acids and neurotransmitter metabolism: expression of cytosolic branched-chain aminotransferase (BCATc) in the cerebellum and hippocampus.

支链氨基酸和神经递质代谢：小脑和海马中胞浆支链转氨酶（BCATc）的表达。

• DOI: 10.1002/cne.20200
• 发表时间: 2004
• 期刊: The Journal of comparative neurology.
• 作者: Sweatt,AndrewJ;Garcia-Espinosa,MariaA;Wallin,Reidar;Hutson,SusanM
• 通讯作者: Hutson,SusanM

Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease.

• DOI: 10.1093/brain/awp024
• 发表时间: 2009-04
• 期刊: Brain : a journal of neurology
• 作者: Zinnanti WJ;Lazovic J;Griffin K;Skvorak KJ;Paul HS;Homanics GE;Bewley MC;Cheng KC;Lanoue KF;Flanagan JM
• 通讯作者: Flanagan JM