NMDA receptor modulation of electrical synapses in the primate brain

这是一项探索性/发展性的提议，旨在研究灵长类动物大脑中电突触的可塑性。作为一个R21，它的目的是评估在一个背景下研究电突触的可行性，这将开辟一个全新的研究领域，可以在2年内探索。这一提议的灵感来自于我们实验室最近的两份报告：1)一份关于猕猴下橄榄神经元起搏电导的稳态可塑性的报告，以及2)一份关于NMDA受体（NMDA- r）激活电突触的报告。我们对啮齿类动物的神经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-Rs在饮用酒精的猕猴的下橄榄中表达上调，这使得这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人员团队，使离体猴电生理学建立起来，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。我们将解决两个基本问题：1。灵长类动物大脑中NMDA-Rs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，因为这将是首次对灵长类动物和自愿上调NMDA-Rs的受试者的电突触进行检查。这些实验的成功完成将开始填补我们在大脑功能知识方面的一个明显空白，这可能对人类健康产生影响。

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.