Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice

γ-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative/hypnotic agents (including neuroactive steroids), anxiety, and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the δ 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 δ subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids.

γ-氨基丁酸A型受体（γ-Aminobutyric acid type A receptors）介导快速抑制性突触传递，其与镇静催眠剂（含神经活性类固醇）、焦虑以及学习记忆的应答过程密切相关。本研究采用基因打靶技术，构建了一株该受体δ亚基缺陷型小鼠。对该缺陷小鼠开展多项行为学体内测试后发现，其对神经活性类固醇的应答出现显著的选择性减弱，而对其他调节类药物的应答则无明显变化。对海马脑片的电生理记录结果显示，纯合缺陷小鼠的微小抑制性突触后电流衰减时程显著加快，但其微小抑制性突触后电流的振幅与频率均未发生明显改变。通过恐惧条件反射实验评估的学习与记忆功能则保持正常。本研究结果首次阐明了δ亚基在GABA药理学以及镇静催眠应答与行为中的全新作用，并为神经活性类固醇的生理学研究提供了新的视角。