Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate typeA receptor delta subunit knockout mice

gamma-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory syn aptic transmission and have been implicated in responses to sedative/hypnot ic agents (including neuroactive steroids), anxiety, and learning and memor y. Using gene targeting technology, we generated a strain of mice deficient in the delta subunit of the GABA type A receptors. In vivo testing of vari ous behavioral responses revealed a strikingly selective attenuation of res ponses to neuroactive steroids, but not to other modulatory drugs. Electrop hysiological recordings from hippocampal slices revealed a significantly fa ster miniature inhibitory postsynaptic current decay time in null mice, wit h no change in miniature inhibitory postsynaptic current amplitude or frequ ency. Learning and memory assessed with fear conditioning were normal. Thes e results begin to illuminate the novel contributions of the delta subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provi de insights into the physiology of neurosteroids.