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At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on γ-aminobutyric acid type A receptor-mediated postsynaptic currents. It has been proposed that distinct molecular mechanisms underlie these dual actions. The authors investigated whether the blocking or the prolonging effect of enflurane is altered by a point mutation (N265M) in the β3 subunit of the γ-aminobutyric acid type A receptor. Furthermore, the role of the β3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated.Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and β3(N265M) mutant mice. The effects of 0.3 and 0.6 mm enflurane on decay kinetics, peak amplitude, and charge transfer were quantified. Furthermore, the impact of enflurane-induced changes in spontaneous action potential firing was evaluated by extracellular recordings in slices from wild-type and mutant mice.In slices derived from wild-type mice, enflurane prolonged inhibitory postsynaptic current decays and decreased peak amplitudes. Both effects were almost absent in slices from β3(N265M) mutant mice. At clinically relevant concentrations between MAC-awake and MAC-immobility, the anesthetic was less effective in depressing spontaneous action potential firing in slices from β3(N265M) mutant mice compared with wild-type mice.At concentrations between MAC-awake and MAC-immobility, β3-containing γ-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The β3(N265M) mutation affects both the prolonging and blocking effects of enflurane on γ-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons.