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.
Prevention of recall during surgery (i.e. amnesia) is a highly desired feature of anesthetic use. Through this application we will investigate the role of NMDA receptor-mediated transmission in anesthetic induced amnesia and quantify the extent of block of NMDA receptor-mediated transmission needed to cause amnesia. The proposed studies will help us understand how anesthetics achieve desired endpoints and will guide the future use and development of anesthetic agents.