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首页> 外文期刊>The European Journal of Neuroscience >Loss of zolpidem efficacy in the hippocampus of mice with the GABA receptor gamma2 F77I point mutation.
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Loss of zolpidem efficacy in the hippocampus of mice with the GABA receptor gamma2 F77I point mutation.

机译：具有GABA受体gamma2 F77I点突变的小鼠海马中唑吡坦功效的丧失。

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Abstract Zolpidem is a hypnotic benzodiazepine site agonist with some gamma-aminobutyric acid (GABA)(A) receptor subtype selectivity. Here, we have tested the effects of zolpidem on the hippocampus of gamma2 subunit (gamma2F77I) point mutant mice. Analysis of forebrain GABA(A) receptor expression with immunocytochemistry, quantitative [(3)H]muscimol and [(35)S] t-butylbicyclophosphorothionate (TBPS) autoradiography, membrane binding with [(3)H]flunitrazepam and [(3)H]muscimol, and comparison of miniature inhibitory postsynaptic current (mIPSC) parameters did not reveal any differences between homozygous gamma2I77/I77 and gamma2F77/F77 mice. However, quantitative immunoblot analysis of gamma2I77/I77 hippocampi showed some increased levels of gamma2, alpha1, alpha4 and delta subunits, suggesting that differences between strains may exist in unassembled subunit levels, but not in assembled receptors. Zolpidem (1 microm) enhanced the decay of mIPSCs in CA1 pyramidal cells of control (C57BL/6J, gamma2F77/F77) mice by approximately 60%, and peak amplitude by approximately 20% at 33-34 degrees C in vitro. The actions of zolpidem (100 nm or 1 microm) were substantially reduced in gamma2I77/I77 mice, although residual effects included a 9% increase in decay and 5% decrease in peak amplitude. Similar results were observed in CA1 stratum oriens/alveus interneurons. At network level, the effect of zolpidem (10 microm) on carbachol-induced oscillations in the CA3 area of gamma2I77/I77 mice was significantly different compared with controls. Thus, the gamma2F77I point mutation virtually abolished the actions of zolpidem on GABA(A) receptors in the hippocampus. However, some residual effects of zolpidem may involve receptors that do not contain the gamma2 subunit.
机译：摘要唑吡坦是一种具有一定γ-氨基丁酸（GABA）（A）受体亚型选择性的催眠性苯二氮杂位激动剂。在这里，我们测试了唑吡坦对γ2亚基（gamma2F77I）点突变小鼠海马的影响。用免疫细胞化学，定量[（3）H]麝香酚和[（35）S]叔丁基双环磷硫酸酯（TBPS）放射自显影，[[3] H]氟硝西m和[（3）的膜结合]分析前脑GABA（A）受体的表达H] muscimol和微型抑制性突触后电流（mIPSC）参数的比较未显示纯合的gamma2I77 / I77和gamma2F77 / F77小鼠之间的任何差异。但是，对gamma2I77 / I77海马体的定量免疫印迹分析显示，gamma2，alpha1，alpha4和delta亚基的水平有所提高，这表明菌株之间的差异可能存在于未组装的亚基水平中，而不存在于组装的受体中。唑吡坦（1微米）在体外在33-34摄氏度下使对照（C57BL / 6J，gamma2F77 / F77）小鼠的CA1锥体细胞中的mIPSC衰减增加了约60％，峰值幅度增加了约20％。唑吡坦（100 nm或1微米）的作用在gamma2I77 / I77小鼠中显着降低，尽管残留效应包括衰减增加9％和峰幅度减少5％。在CA1层中层/肺泡中神经中观察到了相似的结果。在网络一级，唑吡坦（10微米）对卡巴胆碱诱导的gamma2I77 / I77小鼠CA3区域振荡的影响与对照组相比有显着差异。因此，gamma2F77I点突变实际上消除了唑吡坦对海马中GABA（A）受体的作用。但是，唑吡坦的某些残留作用可能涉及不包含gamma2亚基的受体。

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