␥-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative͞hypnotic agents (including neuroactive steroids), anxiety, and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the ␦ subunit of the GABA type A receptors. In vivo testing of various behavioral responses revealed a strikingly selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs. Electrophysiological recordings from hippocampal slices revealed a significantly faster miniature inhibitory postsynaptic current decay time in null mice, with no change in miniature inhibitory postsynaptic current amplitude or frequency. Learning and memory assessed with fear conditioning were normal. These results begin to illuminate the novel contributions of the ␦ subunit to GABA pharmacology and sedative͞hypnotic responses and behavior and provide insights into the physiology of neurosteroids.

ABSTRACT␥-Aminobutyric acid type A receptors (GABA A -Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The ␤3 subunit is an essential component of the GABA A -R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a ␤3 gene inactivated by gene targeting. GABA A -R density is approximately halved in brain of ␤3-deficient mice, and GABA A -R function is severely impaired. Most ␤3-deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. ␤3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the ␤3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. ␤3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and͞or pleiotropic developmental defects.