Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

Abstract

Background γ-aminobutyric acid type A (GABAA) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (non-synaptic). Phasic inhibition is further subdivided into fast (GABAA, fast) and slow (GABAA, slow) IPSCs. By virtue of its dendritic location and kinetics, GABAA, slow has been proposed to control synaptic plasticity and memory. Etomidate is a non-barbiturate, intravenous anesthetic that selectively modulates GABAA receptors and produces amnesia at low doses in vivo. Here we have tested whether correspondingly low concentrations of etomidate in vitro alter GABAA, fast and GABAA, slow phasic inhibition. Methods Electrophysiological recordings were obtained from hippocampal slices prepared from postnatal day 3–8 mice and maintained in organotypic culture for 10–14 days. Etomidate was applied at concentrations corresponding to one-half to four times the half maximal effective concentration that impairs hippocampus-dependent learning and memory – i.e. 0.125 to 1 μM. Results Etomidate 0.25 μM (the half maximal effective concentration) doubled the time constant of decay of GABAA, slow IPSCs but had no detectable effect on GABAA, fast IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 μM etomidate prolonged the time constant of decay by 310% and 410% for GABAA, slow and by 25% and 78% for GABAA, fast. Concentrations of etomidate up to 1 μM had no significant effects on the amplitudes of either GABAA, fast or GABAA, slow IPSCs. Conclusions At concentrations that impair hippocampus-dependent memory, etomidate modulates GABAA, slow more strongly than GABAA, fast IPSCs. Effects of etomidate on GABAA, slow IPSCs may contribute to etomidate-induced amnesia.

Neonatal Propofol and Etomidate Exposure Enhance Inhibitory Synaptic Transmission in Hippocampal Cornus Ammonis 1 Pyramidal Neurons

“…Dai et al . [13] found that etomidate modulates slow IPSCs (GABA A, slow ) more strongly than fast IPSCs (GABA A, fast ) and prolongs the time constant of decay of both GABA A, slow and GABA A, fast , which are involved in etomidate-induced amnesia. However, the GABA tonic alteration after neonatal etomidate exposure was not explored in this study and might need further study.…”

“…The slow time constant of decay of GABA A, slow (30–70 ms) indicates τ2 as opposed to 3–8 ms for GABA A, fast (τ1). [13] Miniature and/or spontaneous inhibitory synaptic current events of each neuron were analyzed and averaged; then, the kinetic indices of different neurons in the same groups were averaged, respectively.…”

“…[11] Etomidate modulates GABA A, slow more strongly than GABA A, fast IPSCs, contributing to etomidate-induced, hippocampus-dependent memory impairment. [13] Our previous study showed that non-N-methyl-D-aspartate (non-NMDA) receptors (glutamate receptor 5 [GluR5]-containing kainate receptor) regulate the inhibitory synaptic transmission through endogenous glutamate, which is involved in age-dependent cognitive decline. [14] However, the research on long-term effects of neonatal propofol and/or etomidate on inhibitory and excitatory neurotransmissions interplay is very sparse, especially concerning the effects of propofol and/or etomidate on the interplay between GABAergic and glutamatergic neurotransmissions.…”

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 GABAA receptor

“…Our analysis of spontaneous GABA A,fast IPSCs showed that they are mediated primarily by β3-GABA A Rs. Also, fast inhibitory currents are relatively insensitive to amnestic concentrations of etomidate (Dai et al, 2009). Taken together, these findings indicate that GABA A , fast inhibition is unlikely to contribute substantially.…”

“…Taken together, these findings indicate that GABA A , fast inhibition is unlikely to contribute substantially. By contrast, GABA A,slow , an inhibitory current that overlaps anatomically with excitatory receptors on the dendrites (Pearce, 1993), was shown previously to engage α5-GABA A Rs (Zarnowska et al, 2009), and to be particularly sensitive to amnestic concentrations of etomidate (Dai et al, 2009). This form of inhibition thus appears to be well suited to anesthetic control of synaptic plasticity and memory.…”