NMDA receptor modulation of electrical synapses in the primate brain

NMDA 受体对灵长类动物大脑中电突触的调节

• 批准号: 8416949
• 负责人: John P Welsh
• 金额: $ 22.2万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416949
• 关键词: Abstinence; Address; Adult; Alcohol consumption; Alcohol withdrawal syndrome; Alzheimer' s Disease; Animal Model; Animals; Area; Behavior; Biological Models; Brain; Brain Stem; Cells; Chemical Synapse; Chemicals; Chronic; Coupled; Coupling; Data; Development; Drug effect disorder; Electrical Synapse; Electrophysiology (science); Feasibility Studies; Goals; Hand; Health; Human; Human Resources; Inferior; Investigation; Knowledge; Laboratories; Life; Macaca; Mediating; Memantine; Modeling; Molecular; Monkeys; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; National Institute of Neurological Disorders and Stroke; Neurons; Olives - dietary; Pharmaceutical Preparations; Positioning Attribute; Primates; Probability; Procedures; Property; Publishing; Receptor Activation; Regulation; Reporting; Rodent; Slice; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Time; Up-Regulation; Whole-Cell Recordings; acamprosate; chronic alcohol ingestion; connexin 36; density; innovation; meetings; neurophysiology; novel; receptor; receptor upregulation; research study

This is an exploratory/developmental proposal to examine plasticity of electrical synapses in the primate brain. As an R21, its purpose is to assess the feasibility of studying electrical synapses in a context that opens up a completely novel area of investigation that can be explored in 2 years. The proposal is inspired by two recent reports from our labs: 1) a report of homeostatic plasticity in the pace-making conductance of macaque inferior olive neurons, and 2) a report that electrical synapses are potentiated by NMDA receptor (NMDA-R) activation. Much is known about the properties of neuronal electrical synapses in rodents, but virtually nothing is known about electrical synapses in the primate brain. Our preliminary data indicate that NMDA-Rs are upregulated in the inferior olive of macaques that consume alcohol, making the inferior olive of such monkeys an innovative model in which to study NMDA-R regulation of electrical synapses. Because all of the challenging techniques and the team of personnel that enable ex vivo monkey electrophysiology are established, we can now explore the properties and plasticity of electrical synapses in the primate brain. We will address 2 fundamental questions: 1. Are electrical synapses potentiated by an upregulation of NMDA-Rs in the primate brain? 2. Do therapeutic NMDA-R antagonists used to treat humans suppress electrical synapses in the primate? We believe that the aims will be groundbreaking, because they would be the first examination of electrical synapses in the primate, and in subjects that voluntarily upregulate their NMDA-Rs. Successful completion of these experiments will begin to fill a conspicuous gap in our knowledge of brain function which could have implications for human health.

这是一项探索性/发展性的提议，旨在检查灵长类动物大脑中电突触的可塑性。作为 R21，其目的是评估在一个可以在 2 年内探索的全新研究领域的背景下研究电突触的可行性。该提案的灵感来自我们实验室最近的两份报告：1）关于猕猴下橄榄神经元起搏电导的稳态可塑性的报告，2）关于电突触通过 NMDA 受体（NMDA-R）激活而增强的报告。人们对啮齿动物神经元电突触的特性了解很多，但对灵长类动物大脑中的电突触几乎一无所知。我们的初步数据表明，NMDA-R 在饮酒的猕猴的下橄榄中表达上调，使此类猴子的下橄榄成为研究 NMDA-R 对电突触调节的创新模型。由于所有具有挑战性的技术和支持离体猴子电生理学的人员团队都已经建立，我们现在可以探索灵长类动物大脑中电突触的特性和可塑性。我们将解决 2 个基本问题： 1. 灵长类动物大脑中 NMDA-R 的上调是否会增强电突触？ 2. 用于治疗人类的治疗性 NMDA-R 拮抗剂是否会抑制灵长类动物的电突触？我们相信这些目标将是开创性的，因为它们将是对灵长类动物以及自愿上调 NMDA-R 的受试者的电突触的首次检查。这些实验的成功完成将开始填补我们对大脑功能知识的明显空白，这可能对人类健康产生影响。