GABAA receptor alpha5 subunits contribute to GABAA,slow synaptic inhibition in mouse hippocampus.
GABAA receptor alpha5 subunits contribute to GABAA,slow synaptic inhibition in mouse hippocampus.
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DOI：
10.1152/jn.91203.2008
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发表时间：
2009-03
影响因子：
2.5
通讯作者：
E. Żarnowska;R. Keist;U. Rudolph;R. Pearce
中科院分区：
文献类型：
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作者：
E. Żarnowska;R. Keist;U. Rudolph;R. Pearce
γ-氨基丁酸A型（GABA（A））受体α 5亚基在海马中大量表达，是改善认知功能的潜在药物靶点。它们存在于突触和突触外部位，并已被证明介导锥体神经元的紧张性抑制。我们测试的假设，α 5亚基也有助于突触抑制，通过测量地西泮（DZ）的自发和刺激诱发的抑制性突触后电流（IPSC）在转基因小鼠携带点突变的α 5亚基（α 5-H105 R），使这些受体不敏感苯二氮卓类药物的影响。在野生型小鼠中，DZ（1 μ M）增加了自发IPSC（sIPSC）和刺激诱发的GABA（A，慢）IPSC（eIPSC）的振幅，并延长了GABA（A，快）sIPSC的衰减。在α 5突变小鼠中，DZ增加了sIPSC（<50 pA）和eIPSC（<300 pA）GABA（A，慢）的小振幅子集的振幅，并延长了GABA（A，快）sIPSC的衰减，但未能增加较大sIPSC和eIPSC GABA（A，慢）的振幅。这些结果表明，α 5亚基有助于GABA（A，慢）突触的大振幅子集，并暗示这些突触在认知功能的调制由靶向α 5亚基的药物。
gamma-Aminobutyric acid type A (GABA(A)) receptor alpha5 subunits, which are heavily expressed in the hippocampus, are potential drug targets for improving cognitive function. They are found at synaptic and extrasynaptic sites and have been shown to mediate tonic inhibition in pyramidal neurons. We tested the hypothesis that alpha5 subunits also contribute to synaptic inhibition by measuring the effect of diazepam (DZ) on spontaneous and stimulus-evoked inhibitory postsynaptic currents (IPSCs) in genetically modified mice carrying a point mutation in the alpha5 subunit (alpha5-H105R) that renders those receptors insensitive to benzodiazepines. In wild type mice, DZ (1 microM) increased the amplitude of spontaneous IPSCs (sIPSCs) and stimulus-evoked GABA(A,slow) IPSCs (eIPSCs) and prolonged the decay of GABA(A,fast) sIPSCs. In alpha5-mutant mice, DZ increased the amplitude of a small-amplitude subset of sIPSCs (<50 pA) and eIPSCs (<300 pA) GABA(A,slow) and prolonged the decay of GABA(A,fast) sIPSCs, but failed to increase the amplitude of larger sIPSCs and eIPSCs GABA(A,slow). These results indicate that alpha5 subunits contribute to a large-amplitude subset of GABA(A,slow) synapses and implicate these synapses in modulation of cognitive function by drugs that target alpha5 subunits.