Title: Etomidate impairs long-term potentiation in vitro by targeting α5-GABAARs on non-pyramidal cells
Legend: Left – Immunohistochemical detection of the GABAAR a5subunit in the hippocampus of conditional and global a5 KO mice. Right – Electrophysiology. LTP is suppressed by etomidate in fl–a5 (pseudo-wild type) and CA1-pyr-a5–KO mice but not gl–a5–KO mice. A, Etomidate (Etom) suppressed LTP in brain slices from fl–a5 mice. A theta burst stimulus (TBS) was delivered at time 0. Control (Ctrl) experiments were performed in drug-free conditions. Etomidate experiments were performed in the continuous presence of etomidate at the indicated concentrations, in brain slices that had been equilibrated with etomidate for at least 1 h before initiating the recording. Data points indicate mean±SEM. Inset traces show representative field EPSPs (fEPSPs) recorded before TBS (thick lines) and 60 min after TBS (thin lines).B, Etomidate did not suppress LTP in brain slices from gl–a5–KO mice. C, Etomidate suppressed LTP in brain slices from CA1–pyr–a5–KO mice 8 weeks (gray circles) and 16-weeks-old (gray squares). D, Summary of LTP results. Bars show fEPSP slope (mean±SEM) during the last 11 min (50–60 min) of recording. *p<0.05, **p<0.01. These results show that removal of a5 subunits from pyramidal cells does not reproduce the global KO phenotype, suggesting that a5 subunits on other cells (i.e. interneurons or glia) are the targets of etomidate for suppressing memory formation.
Citation: Rodgers, F. C., Zarnowska, E. D., Laha, K.T., Engin, E., Zeller, A., Keist, R., Rudolph, U., Pearce, R. A. (2015) Etomidate impairs long-term potentiation in vitro by targeting α5-GABAARs on non-pyramidal cells. Journal of Neuroscience 35: 9707-16. PMCID: PMC4571505
Abstract: Previous experiments using genetic and pharmacological manipulations have provided strong evidence that etomidate impairs synaptic plasticity and memory by modulating a5-subunit containing GABAARs (a5-GABAARs). Since a5-GABAARs mediate tonic inhibition (TI) in hippocampal CA1 pyramidal cells, and etomidate enhances TI, etomidate enhancement of TI in pyramidal cells has been proposed as the underlying mechanism (Martin et al., 2009). Here we tested this hypothesis by selectively removing a5-GABAARs from pyramidal neurons (CA1-pyr-a5-KO) and comparing the ability of etomidate to enhance TI and block LTP in fl-a5 (WT), global-a5-KO (gl-a5-KO), and CA1-pyr-a5-KO mice. Etomidate suppressed LTP in slices from WT and CA1-pyr-a5-KO but not gl-a5-KO mice. There was a trend toward reduced TI in both gl-a5-KO and CA1-pyr-a5-KO mice, but etomidate enhanced TI to similar levels in all genotypes. The dissociation between effects of etomidate on TI and LTP in global-a5KO indicates that increased TI in pyramidal neurons is not the mechanism by which etomidate impairs LTP and memory. Rather, the ability of etomidate to block LTP in WT and CA1-pyr-a5-KO mice, but not in gl-a5-KO mice, points toward a5-GABAARs on non-pyramidal neurons as the essential effectors controlling plasticity in this in vitro model of learning and memory.
About the Lab: Research in the Pearce laboratory is focused on the mechanisms by which general anesthetics alter brain function. We are particularly interested in understanding how modulation of GABAA receptors impairs memory – a fundamental endpoint of anesthesia. For our studies we utilize expressed recombinant receptors and hippocampal brain slices to investigate the roles of specific subunit combinations and cell types in the control of learning and memory.