General anesthetic modulation of memory through alpha5-GABA(A) receptors on Lamp5-expressing interneurons

Project Summary/Abstract The long-term objective of the research is to understand the mechanism of general anesthesia, relating specific molecular- and cellular-level targets to their behavioral-level consequences. This proposal focuses on the role of hippocampal GABAA receptors in the suppression of learning and memory. Three specific aims test the hypotheses that etomidate and other general anesthetics suppress memory by targeting 5-GABAARs on Lamp5-expressing interneurons (Lamp5-INs), that they do so through an excitatory action on the axons of Lamp5-INs, and that they enhance memory by targeting one of the classes of non-Cck-INs. Specific Aim 1) Test the role of 5-GABAARs on Lamp5-INs in etomidate modulation of inhibitory neurotransmission and memory, studying mice in which 5-GABAARs have been eliminated from Lamp5-expressing interneurons, testing effects of etomidate on contextual conditioning, on place cell and spatial engram formation as neural correlates of hippocampal memory, and on anesthetic-induced changes in neurotransmission. Specific Aim 2) Identify the interneuron subtype(s) that counteract Cck-INs to enhance memory, studying mice in which 5-GABAARs have been eliminated using combinations of Cre-drivers. Specifc Aim 3) Test whether other anesthetics suppress memory through 5-GABAARs on Lamp5-INs, studying effects of propofol, midazolam, sevoflurane, and ketamine on contextual conditioning and place cell and spatial engram formation in mice in which 5-GABAARs have been eliminated from Lamp5-expressing interneurons. Overall, the experiments will further our understanding of the mechanisms by which anesthetics suppress learning. More broadly, they will contribute to our basic understanding of how memory is supported and controlled by interneurons. Given the essential role of interneurons in circuit function, the results will have widespread application to learning deficits in Alzheimer’s disease and numerous other diseases associated with impairments of learning and memory.