The role of excitatory synaptic transmission in anesthetic induced amnesia

描述(申请人提供)：全身麻醉药有许多分子靶点，包括配基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、意识丧失和静止的能力的基础；然而，对于哪些靶点对于调节麻醉行为是必不可少的，以及每个靶点对不同行为终点的相对重要性，我们缺乏了解。这一建议的主要目的是了解兴奋性突触传递的调节，更具体地说，NMDA受体介导的传递，是如何与麻醉剂诱导的遗忘症联系起来的。尽管许多体内研究表明NMDA拮抗剂具有损害记忆的能力，但尚不清楚需要阻断多少NMDA受体介导的传递才能导致健忘。使用一种选择性的NMDA受体拮抗剂，我们将在损害学习和记忆的剂量下测定该拮抗剂在小鼠大脑中的浓度，然后在体外，使用海马脑片记录，我们将确定所确定的浓度在多大程度上抑制NMDA受体介导的传递。NMDA介导的突触传递的调节是否也是广泛使用的吸入麻醉剂异氟醚引起的遗忘的部分或全部原因尚不清楚。因此，我们将确定与遗忘浓度的异氟醚相关的兴奋性突触传递的调制量。目的是建立麻醉剂在突触水平和行为水平的作用之间的定量关系。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性遗忘中所起的作用。

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.