Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice
Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice
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DOI：
10.1073/pnas.96.22.12905
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Homanics, GE
中科院分区：
文献类型：
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作者：
Mihalek, RM;Banerjee, PK;Homanics, GE
γ-氨基丁酸 (GABA) A 型受体介导快速抑制性突触传递，并与镇静/催眠药物（包括神经活性类固醇）、焦虑以及学习和记忆的反应有关。利用基因打靶技术，我们培育出了一种缺乏 GABA A 型受体 delta 亚基的小鼠品系。对各种行为反应的体内测试表明，对神经活性类固醇的反应有显着的选择性减弱，但对其他调节药物的反应却没有。海马切片的电生理记录显示，空白小鼠的微型抑制性突触后电流衰减时间明显更快，而微型抑制性突触后电流幅度或频率没有变化。通过恐惧调节评估的学习和记忆是正常的。这些结果开始阐明 delta 亚基对 GABA 药理学和镇静/催眠反应和行为的新贡献，并为神经类固醇的生理学提供了见解。
gamma-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 delta 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 delta subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids.