Glutamate transport regulation and synaptic plasticity

谷氨酸转运调节和突触可塑性

• 批准号: 6365725
• 负责人: ARNOLD none ESKIN
• 金额: $ 32万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6365725
• 关键词: Aplysia; NMDA receptors; electrophysiology; glutamate transporter; glutamine; hippocampus; intracellular transport; laboratory mouse; laboratory rat; leucine; long term potentiation; neural plasticity; neurophysiology; neuroregulation; neurotransmitter metabolism; protein kinase C

A number of properties of a neuron change in a coordinated fashion to store a given type of memory. Our long- term goal is to determine which properties of neurons change, and how these properties are regulated during formation of memories. Regulation of glutamate transporter activity may be necessary during increases in synaptic efficacy to maintain the fidelity of synaptic transmission and to avoid toxicity that might occur if glutamate is elevated in the synaptic cleft for too long. Thus, we hypothesize that increases in glutamate transporter activity will accompany increases in synaptic efficacy at glutamatergic synapses, especially ones involving long-term changes in synaptic efficacy. This hypothesis will be tested in vitro by investigating regulation of glutamate uptake after induction of LTP and in vivo by investigating regulation of glutamate uptake after contextual fear conditioning. Area CA1 of the rat hippocampus will be used in most experiments. We will use a multidisciplinary approach including electrophysiology, biochemistry and behavioral analysis to investigate the regulation of glutamate uptake. The proposed research has four specific aims. Most of the experiments in Specific Aims 1-3 will investigate regulation of glutamate transport during two different forms of LTP (E- and L-LTP). Aim 1 is to characterize the mechanisms involved in the increase in glutamate uptake produced by high frequency stimulation. Aim 2 is to determine whether induction of LTP increases the expression of glutamate transporters, and what mechanisms are involved in the increase in expression. Aim 3 is to investigate the relationship between LTP and changes in glutamate uptake and expression of glutamate transporters. Aim 4 is to determine whether an associative learning paradigm, contextual fear conditioning, produces an increase in glutamate transport in the hippocampus in vivo. In our lab, recent studies have shown that glutamate uptake is regulated during long-term memory in Aplysia, and preliminary results indicate that glutamate uptake is regulated during LTP in the rat hippocampus as well. Thus, the results of these studies will likely indicate that regulation of glutamate transport is a general phenomenon at glutamatergic synapses involved in synaptic plasticity. As glutamate is a remarkably potent and rapidly acting neurotoxin, fundamental studies of long-term regulation of glutamate transport should aid solutions to brain trauma and diseases such as amyotrophic lateral sclerosis.

神经元的许多属性都以协调的方式改变，以存储给定类型的内存。 我们的长期目标是确定神经元的哪些特性发生变化，以及在记忆形成过程中如何调节这些特性。在突触效果提高以维持突触传播的忠诚度期间，可能需要调节谷氨酸转运蛋白活性，并避免突触裂口中谷氨酸升高太长的毒性。因此，我们假设谷氨酸转运蛋白活性的增加将伴随着谷氨酸能突触的突触功效的提高，尤其是涉及突触功效的长期变化的突触。 该假设将在体外通过研究LTP和体内诱导谷氨酸摄取的调节，通过研究环境恐惧调节后的谷氨酸摄取来调节谷氨酸的摄取。 大鼠海马的面积CA1将用于大多数实验。 我们将使用包括电生理学，生物化学和行为分析在内的多学科方法来研究谷氨酸摄取的调节。 拟议的研究具有四个具体目标。 特定目标1-3中的大多数实验将在两种不同形式的LTP（E-和L-LTP）中研究谷氨酸转运的调节。 目的1是表征高频刺激产生的谷氨酸摄取量增加的机制。 AIM 2是确定LTP的诱导是否会增加谷氨酸转运蛋白的表达，以及在表达增加中涉及哪些机制。 目的3是研究LTP与谷氨酸摄取和谷氨酸转运蛋白表达的变化之间的关系。 AIM 4是确定关联学习范式，情境恐惧调节是否会导致体内海马中的谷氨酸运输增加。 在我们的实验室中，最近的研究表明，谷氨酸摄取在高脂长期记忆期间受到调节，初步结果表明，在大鼠海马的LTP期间，在LTP期间调节谷氨酸摄取。 因此，这些研究的结果可能表明，谷氨酸转运的调节是与突触可塑性有关的谷氨酸能突触的一般现象。 由于谷氨酸是一种非常有效且迅速起作用的神经毒素，因此对谷氨酸转运的长期调节的基本研究应有助于解决脑外伤和疾病（例如肌萎缩性侧面硬化症）。