Isoflurane enhances both fast and slow synaptic inhibition in the hippocampus at amnestic concentrations.
Isoflurane enhances both fast and slow synaptic inhibition in the hippocampus at amnestic concentrations.
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DOI：
10.1097/aln.0b013e31824be0e3
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发表时间：
2012-04
期刊：
影响因子：
8.8
通讯作者：
Pearce RA
中科院分区：
文献类型：
--
作者：
Dai S;Perouansky M;Pearce RA
γ-氨基丁酸A型（GABAA）受体介导的抑制作用一直被认为是多种全麻药的重要靶点。在海马体中，两种GABAA受体介导的阶段性抑制共存：GABAA为快速抑制，主要表达于体周部位；GABAA为缓慢抑制，主要表达于树突。它们在空间上的分离表明GABAA具有不同的功能：慢GABAA控制树突突触的可塑性，快GABAA控制胞体动作电位的启动。我们研究了在失忆症浓度下异氟醚对GABAA、快速和缓慢抑制的调节，并将其与行为等效剂量的GABAA受体选择性药物依托咪酯的调节进行了比较。在近生理温度下，对C57BL/6 x 129/SvJ F1杂交小鼠的器官型海马锥体细胞进行全细胞记录。利用谷氨酸受体拮抗剂分离GABAA受体介导的电流。电刺激可诱发腔隙层分子内的GABAA、慢电流。在河豚毒素存在的情况下，记录了微型GABAA，快速电流。100µM异氟醚（约EC50，健忘症）减缓快速和缓慢抑制性突触后电流衰减约25%。较高的浓度，高达400 μ M，在不改变电流振幅的情况下，按比例产生更大的效果。对GABAA的影响，大约是同等浓度依托咪酯产生的效果的一半。在失忆症浓度下，异氟醚增强了两种类型的阶段性GABAA受体介导的抑制，其程度相似。这种模式不同于依托咪酯，它在低浓度下选择性地增强缓慢抑制。异氟醚的这些作用是足够大的，它们可能在很大程度上有助于抑制海马的学习和记忆。
Inhibition mediated by γ-aminobutyric acid type A (GABAA) receptors has long been considered an important target for a variety of general anesthetics. In the hippocampus, two types of phasic GABAA receptor-mediated inhibition coexist: GABAA,fast, which is expressed primarily at peri-somatic sites, and GABAA,slow, which is expressed primarily in the dendrites. Their spatial segregation suggests distinct functions: GABAA,slow may control plasticity of dendritic synapses, while GABAA,fast controls action potential initiation at the soma. We examined modulation of GABAA,fast and GABAA,slow inhibition by isoflurane at amnesic concentrations, and compared it to modulation by behaviorally equivalent doses of the GABAA receptor-selective drug etomidate. Whole-cell recordings were conducted at near-physiological temperature from pyramidal cells in organotypic hippocampal cultures obtained from C57BL/6 x 129/SvJ F1 hybrid mice. GABAA receptor-mediated currents were isolated using glutamate receptor antagonists. GABAA,slow currents were evoked by electrical stimulation in the stratum lacunosum-moleculare. Miniature GABAA,fast currents were recorded in the presence of tetrodotoxin. 100 µM isoflurane (approximately EC50,amnesia) slowed fast and slow inhibitory postsynaptic current decay by approximately 25%. Higher concentrations, up to 400 µM, produced proportionally greater effects without altering current amplitudes. The effects on GABAA,slow were approximately one-half those produced by equi-amnesic concentrations of etomidate. Isoflurane enhances both types of phasic GABAA receptor-mediated inhibition to similar degrees at amnesic concentrations. This pattern differs from etomidate, which at low concentrations selectively enhances slow inhibition. These effects of isoflurane are sufficiently large that they may contribute substantially to its suppression of hippocampal learning and memory.