Although anesthetics have been widely used for over a century, their molecular actions are poorly understood. The main target of general anesthetics is thought to be the gamma-aminobutyric acid subtype A receptor (GABAAR), which mediates for fast inhibitory signaling in the central nervous system. We previously showed that the tonic current mediated by extrasynaptic alpha5 subunit containing GABAARs (alpha5GABAARs) is sensitive to low concentrations of anaesthetics. Here, we examined the contribution of alpha5GABAARs to amnesia induced by the general anesthetic, etomidate. Whole-cell patch clamp studies showed that etomidate selectively enhanced a tonic current in wildtype but not alpha5GABAARs null mutant (alpha5-/-) hippocampal pyramidal neurons. Behavioral studies determined that etomidate impaired the performance of wildtype but not alpha5-/- mice for hippocampal-dependent learning and memory tasks. Together, these results suggest that alpha5GABAARs may play an important role in learning and memory processes and the amnestic effects of etomidate.