Opposing actions of etomidate on cortical theta oscillations are mediated by different γ-aminobutyric acid type A receptor subtypes

Abstract

Background: Cortical networks generate diverse patterns of rhythmic activity. Theta oscillations (4-12 Hz) are commonly observed during spatial learning and working memory tasks. The authors ask how etomidate, acting predominantly via γ-aminofoutyric acid type A (GABAA) receptors containing β2 or β3 subunits, affects theta activity in vitro. Methods: To characterize the effects of etomidate, the authors recorded action potential firing together with local field potentials in slice cultures prepared from the neocortex of the β3(N265M) knock-in mutant and wild type mice. Actions of etomidate were studied at 0.2 μM, which is approximately 15% of the concentration causing immobility (∼1.5 μM). Results: In preparations derived from wild type and β3(N265M) mutant mice, episodes of ongoing activity spontaneously occurred at a frequency of approximately 0.1 Hz and persisted for several seconds. Towards the end of these periods, synchronized oscillations in the theta band developed. These oscillations were significantly depressed in slices from β3(N265M) mutant mice (P < 0.05). In this preparation etomidate acts almost exclusively via β2 subunit containing GABAA receptors. In contrast, no depression was observed in slices from wild type mice, where etomidate potentiates both β2- and β3-containing GABAA receptors. Conclusions: At concentrations assumed to cause sedation and amnesia, etomidate depresses theta oscillations via β2-containing GABAA receptors but enhances these oscillations by acting on β3 subunit containing receptors. This indicates that the overall effect of the anesthetic reflects a balance between enhancement and inhibition produced by different GABAA receptor subtypes.