The role of excitatory synaptic transmission in anesthetic induced amnesia

描述（由申请人提供）：全身麻醉剂有许多分子靶点，包括配体门控和电压门控离子通道，这些靶点的调节导致抑制性神经传递的增强或兴奋性神经传递的抑制。这些效应被认为是麻醉药产生健忘症、无意识和不动能力的基础；然而，关于哪些靶点是介导麻醉作用所必需的以及每个靶点对不同行为终点的相对重要性的知识是缺乏的。本研究的主要目的是了解兴奋性突触传递的调节，特别是NMDA受体介导的传递，是如何与麻醉诱导的健忘症联系在一起的。尽管大量的体内研究表明NMDA拮抗剂能够损害记忆，但尚不清楚需要阻断多少NMDA受体介导的传递才能导致失忆。使用选择性NMDA受体拮抗剂，我们将在小鼠的大脑中确定拮抗剂的浓度，在损害学习和记忆的剂量下，然后在体外，使用海马脑切片记录，我们将确定确定的浓度抑制NMDA受体介导的传播的程度。nmda介导的突触传递的调节是否也部分或完全导致了广泛使用的吸入麻醉剂异氟醚引起的健忘症尚不清楚。因此，我们将确定与健忘浓度异氟醚相关的兴奋性突触传递的调制量。目的是建立麻醉药在突触水平和行为水平之间的定量关系。这些研究将提高我们对麻醉药作用的理解，并确定兴奋性突触传递的调节在麻醉诱导的健忘症中所起的作用。

DESCRIPTION (provided by applicant): General anesthetics have numerous molecular targets, including ligand-gated and voltage-gated ion channels, and modulation of these targets results in either an enhancement of inhibitory neurotransmission or a suppression of excitatory neurotransmission. These effects are expected to underlie the capacity of anesthetics to produce amnesia, unconsciousness, and immobility; however, knowledge of which targets are essential for mediating anesthetic actions and the relative importance of each target to different behavioral endpoints is lacking. The primary goal of this proposal is to understand how modulation of excitatory synaptic transmission, and more specifically NMDA receptor- mediated transmission, is connected to anesthetic-induced amnesia. Although numerous in vivo studies have shown the ability of NMDA antagonists to impair memory, it is not clear how much NMDA receptor-mediated transmission needs to be blocked to cause amnesia. Using a selective NMDA receptor antagonist we will determine the concentration of the antagonist in the brain of mice at doses that impair learning and memory and then in vitro, using hippocampal brain slice recording, we will determine how much the determined concentration suppresses NMDA receptor-mediated transmission. Whether the modulation of NMDA-mediated synaptic transmission also contributes in part or completely to amnesia induced by the widely used inhaled anesthetic isoflurane is unknown. Therefore we will determine the amount of modulation of excitatory synaptic transmission associated with an amnestic concentration of isoflurane. The objective is to establish a quantitative relationship between the actions of anesthetics at the synaptic level to the behavioral level. These studies will improve our understanding of the actions of anesthetics and identify what role the modulation of excitatory synaptic transmission plays in anesthetic induced amnesia.