It is widely believed that the general anesthetic, etomidate, depresses neuronal excitability by allosterically modulating postsynaptic GABAA receptors (GABAARs) and increasing inhibitory synaptic transmission. Hippocampal pyramidal neurons generate two forms of GABAergic inhibition including transient postsynaptic currents and a persistent “tonic” conductance. We recently showed that GABAARs containing the α5 subunit (α5GABAARs) generate the tonic but not synaptic currents in murine CA1 pyramidal neurons (PNAS 101:3662). Further, low concentrations of etomidate selectively enhance the tonic but not synaptic currents in hippocampal neurons (SFN Abstract 2003 #571.2). To test the hypothesis that etomidate increases the tonic current by modulating α5GABAARs, we examined the effects of etomidate in neurons from wildtype (α5+/+) and α5 subunit null mutant mice (α5-/-). Hippocampal neurons from postnatal mice (P1) were grown in dissociated cultures and examined using standard whole-cell recording methods (Vm -6...