Metabolism and Excitability in Rodent Hippocampus

啮齿动物海马的代谢和兴奋性

• 批准号: 6774428
• 负责人: ANNE WILLIAMSON
• 金额: $ 26.47万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774428
• 关键词: Krebs' cycle; astrocytes; blood brain barrier; electrodes; enzyme inhibitors; excitatory aminoacid; gamma aminobutyrate; glutamate ammonia ligase; glutamates; glutamine; hippocampus; isomer; laboratory rat; mass spectrometry; neural inhibition; neural plasticity; neural transmission; neurons; neuroregulation; neurotransmitter antagonist; neurotransmitter metabolism; neurotransmitter transport; sulfur aminoacid

DESCRIPTION (provided by applicant): Both excitatory and inhibitory synaptic transmission rely on the supply of glutamate. Glutamate is synthesized de novo from glucose and also recycled through the glutamate-glutamine cycle between neurons and astrocytes. GABA used for synaptic transmission is also dependent on neuronal-glial cycling as GABA is synthesized from glutamate which can enter interneurons either via uptake or through glutamine. The main goal of this proposal is to test the broad hypothesis that cellular excitability is intimately tied to the status of glutamate-glutamine-GABA cycling and specifically that GABAergic transmission is more sensitive than excitatory transmission to disruption in cycling during periods of sustained neuronal activity because of the added energy-dependent steps needed for the synthesis of GABA. In Specific Aim 1 we will interrupt cycling a several different levels including blockade of the synthetic enzymes of glutamine, glutamate and GABA as well as by blocking glutamine uptake. The effect of these metabolic inhibitors on synaptic inhibition will be examined physiologically. In Specific Aim 2, we will use mass spectometry to measure the changes in the levels of glutamate, glutamine and GABA induced by alterations in neurotransmitter cycling in both the tissue and in the bathing medium to address the time-dependent changes in transmitter levels. In Specific Aim 3 will use 13C isomer spectroscopy to assess the effect of those compounds that cross the blood brain barrier (the GS inhibitor methionine sulfoximine and the glutamine transporter MeAIB) on glutamate-glutamine-GABA cycling in control animals. These experiments should provide important data on the regulation of normal synaptic transmission as well as an understanding of the pathology of a number of neurological disorders where changes in neural energetics have been seen including epilepsy, ALS and Huntington's disease.

描述（由申请人提供）：兴奋性和抑制性突触传播都取决于谷氨酸的供应。谷氨酸是从葡萄糖中合成的，也通过神经元和星形胶质细胞之间的谷氨酸谷氨酰胺循环回收。用于突触传播的GABA还取决于神经元循环，因为GABA是从谷氨酸合成的，该谷氨酸可以通过摄取或通过谷氨酰胺进入中间神经元。该提议的主要目的是检验广泛的假设，即细胞兴奋性与谷氨酸谷氨酰胺-GABA循环的状态密切相关，特别是，GABAergic的传播比在持续神经活动期间循环中的兴奋性传播更为敏感，这是由于增加了能量依赖性步骤，因为需要添加能量依赖性的gaba，而Gaba a gaba a gaba a gaba a则需要增加。在特定的目标1中，我们将中断几个不同的水平，包括阻断谷氨酰胺，谷氨酸和GABA的合成酶，以及通过阻断谷氨酰胺的摄取。这些代谢抑制剂对突触抑制的影响将在生理上检查。 在特定的目标2中，我们将使用质量谱法测量谷氨酸，谷氨酰胺和GABA水平的变化，这些变化是通过在组织和沐浴培养基中神经递质循环的改变引起的，以解决递归发射机水平的时间依赖性变化。 在特定目标中，3将使用13C异构体光谱法来评估那些跨越血脑屏障的化合物（GS抑制剂甲硫氨酸硫胺和谷氨酰胺转运蛋白MEAIB）对对照动物中谷氨酸 - 谷氨酰胺-GABA循环的影响。 这些实验应提供有关调节正常突触传播的重要数据，以及对许多神经系统疾病的病理的理解，在这些神经系统疾病中，已经看到神经能量的变化，包括癫痫，ALS和亨廷顿氏病。