RATIONALE: This is an application for funding of a study on the role of extrasynaptic alpha5-containing GABA-A receptors in the CA1 and CA3 subfields and in dentate gyrus and inhibitory hippocampal networks for the amnestic action of the general anesthetic etomidate, using a combination of genetic, behavioral and electrophysiological methods. In his previous position at the University of Zurich, by the generation and analysis of mice carrying a point mutation in the alpha5 subunit of the GABA-A receptor, which leads to a partial knockout of this subunit, the applicant's group demonstrated that GABA-A receptors containing the alpha5 subunit modulate defined memory functions. Using novel animal models that have recently been developed in the applicant's laboratory, we propose to characterize the physiological and pharmacological functions of the alpha5 subunit in CA1 and CA3 pyramidal cells and dentate gyrus granule cells of the hippocampus, respectively, using a combination of genetic, electrophysiological, pharmacological, and behavioral techniques, with the major focus on the mechanism of the amnestic actions of general anesthetics.
Intraoperative awareness during general anesthesia has been suggested to occur with an incidence of 0.13% translating to approximately 26,000 cases per year in the United States. The proposal is directed at elucidating the mechanism of action of general anesthetics on learning and memory and the hippocampal inhibitory networks mediating this effect and is expected to lead to novel therapeutic strategies for the development of amnestic drugs to be used in general anesthesia, for the treatment of posttraumatic stress disorder, and potentially also for the development of memory-enhancing drugs e.g. for the treatment of Alzheimer's disease.
|Benham, Rebecca S; Engin, Elif; Rudolph, Uwe (2014) Diversity of neuronal inhibition: a path to novel treatments for neuropsychiatric disorders. JAMA Psychiatry 71:91-3|
|Rudolph, Uwe; Mohler, Hanns (2014) GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol 54:483-507|
|Drexler, Berthold; Zinser, Stefan; Huang, Shengming et al. (2013) Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states. Eur J Pharmacol 703:18-24|
|Straub, Carolin J; Lau, Hew Mun; Parlato, Rosanna et al. (2013) Bidirectional regulation of intravenous general anesthetic actions by ýý3-containing ýý-aminobutyric acid A receptors. Anesthesiology 118:562-76|
|Drexler, Berthold; Antkowiak, Bernd; Engin, Elif et al. (2011) Identification and characterization of anesthetic targets by mouse molecular genetics approaches. Can J Anaesth 58:178-90|
|Rudolph, Uwe; Knoflach, Frederic (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov 10:685-97|