Glutamate transport regulation and synaptic plasticity

谷氨酸转运调节和突触可塑性

• 批准号: 6641222
• 负责人: ARNOLD none ESKIN
• 金额: $ 25.81万
• 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/6641222
• 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.

神经元的许多属性以协调的方式变化以存储给定类型的记忆。 我们的长期目标是确定神经元的哪些特性发生变化，以及这些特性在记忆形成过程中如何受到调节。在突触功效增加过程中，可能需要调节谷氨酸转运蛋白活性，以维持突触传递的保真度，并避免突触间隙中谷氨酸升高时间过长可能发生的毒性。因此，我们假设谷氨酸转运蛋白活性的增加将伴随谷氨酸能突触突触功效的增加，尤其是涉及突触功效长期变化的突触功效。 该假设将通过研究 LTP 诱导后谷氨酸摄取的调节进行体外测试，并通过研究情境恐惧调节后谷氨酸摄取的调节进行体内测试。 大多数实验将使用大鼠海马的 CA1 区。 我们将采用包括电生理学、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。 拟议的研究有四个具体目标。 具体目标 1-3 中的大多数实验将研究两种不同形式的 LTP（E-LTP 和 L-LTP）期间谷氨酸转运的调节。 目标 1 是表征高频刺激产生的谷氨酸吸收增加所涉及的机制。 目标 2 是确定 LTP 的诱导是否会增加谷氨酸转运蛋白的表达，以及表达增加涉及哪些机制。 目标 3 是研究 LTP 与谷氨酸摄取和谷氨酸转运蛋白表达变化之间的关系。 目标 4 是确定联想学习范式（情境恐惧调节）是否会增加体内海马体中谷氨酸的转运。 我们实验室最近的研究表明，海兔的长期记忆过程中谷氨酸的摄取受到调节，初步结果表明，大鼠海马的 LTP 过程中谷氨酸的摄取也受到调节​​。 因此，这些研究的结果可能表明，谷氨酸转运的调节是参与突触可塑性的谷氨酸能突触的普遍现象。 由于谷氨酸是一种非常有效且快速作用的神经毒素，因此对谷氨酸转运的长期调节的基础研究应该有助于解决脑外伤和肌萎缩侧索硬化症等疾病。