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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-E (02))
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Cole, Alison E
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Mclean Hospital
United States
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Engin, Elif; Benham, Rebecca S; Rudolph, Uwe (2018) An Emerging Circuit Pharmacology of GABAA Receptors. Trends Pharmacol Sci 39:710-732
Balk, Monika; Hentschke, Harald; Rudolph, Uwe et al. (2017) Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices. Sci Rep 7:3503
Antkowiak, Bernd; Rudolph, Uwe (2016) New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by ?-aminobutyric acid A receptors. Curr Opin Anaesthesiol 29:447-53
Deprez, Francine; Vogt, Fabia; Floriou-Servou, Amalia et al. (2016) Partial inactivation of GABAA receptors containing the ?5 subunit affects the development of adult-born dentate gyrus granule cells. Eur J Neurosci 44:2258-71
Engin, Elif; Zarnowska, Ewa D; Benke, Dietmar et al. (2015) Tonic Inhibitory Control of Dentate Gyrus Granule Cells by ?5-Containing GABAA Receptors Reduces Memory Interference. J Neurosci 35:13698-712
Rodgers, F Clifford; Zarnowska, Ewa D; Laha, Kurt T et al. (2015) Etomidate Impairs Long-Term Potentiation In Vitro by Targeting ?5-Subunit Containing GABAA Receptors on Nonpyramidal Cells. J Neurosci 35:9707-16
Zarnowska, E D; Rodgers, F C; Oh, I et al. (2015) Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABA(A) receptor. Neuropharmacology 93:171-178
Rudolph, Uwe; Möhler, Hanns (2014) GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol 54:483-507
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
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

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