Propofol Affects Cortico-Hippocampal Interactions via β3 Subunit-Containing GABAAReceptors

Background: General anesthetics depress neuronal activity. The depression and uncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However, the molecular targets involved in this process are not fully characterized. GABA(A)receptors, especially the type with beta 3 subunits, represent a main molecular target of propofol. We therefore hypothesized that GABA(A)receptors with beta 3 subunits mediate the propofol-induced disturbance of cortico-hippocampal interactions. Methods: We used local field potential (LFP) recordings from chronically implanted cortical and hippocampal electrodes in wild-type and beta 3(N265M) knock-in mice. In the beta 3(N265M) mice, the action of propofol via beta 3subunit containing GABA(A)receptors is strongly attenuated. The analytical approach contained spectral power, phase locking, and mutual information analyses in the 2-16 Hz range to investigate propofol-induced effects on cortico-hippocampal interactions. Results: Propofol caused a significant increase in spectral power between 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in the beta 3(N265M) mutant. Propofol strongly decreased phase locking of 6-12 Hz oscillations in wild-type mice. This decrease was attenuated in the beta 3(N265M) mutant. Finally, propofol reduced the mutual information between 6-16 Hz in wild-type mice, but only between 6 and 8 Hz in the beta 3(N265M) mutant. Conclusions: GABA(A)receptors containing beta 3 subunits contribute to frequency-specific perturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions of propofol.