NMDA receptor modulation of electrical synapses in the primate brain

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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.