Modulation of GABAA receptors in cerebellar granule neurons by ethanol:: a review of genetic and electrophysiological studies
Modulation of GABAA receptors in cerebellar granule neurons by ethanol:: a review of genetic and electrophysiological studies
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DOI：
10.1016/j.alcohol.2007.04.004
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发表时间：
2007-05-01
期刊：
影响因子：
2.3
通讯作者：
Valenzuela, C. Fernando
中科院分区：
文献类型：
--
作者：
Botta, Paolo;Radcliffe, Richard A.;Valenzuela, C. Fernando
小脑颗粒神经元（CGN）接受来自高尔基体细胞的抑制性输入，其形式为分别由突触后和突触外γ-氨基丁酸A型（GABA（A））受体介导的相位电流和强直电流。突触外受体被认为含有040亚基。在这里，我们回顾了乙醇（EtOH）调制这些受体的研究，这产生了矛盾的结果。尽管对非洲爪蟾卵母细胞中表达的重组受体的研究表明，急性暴露于低浓度（>= 3 mM）乙醇可有效增强α（6）β（3）δ受体，但当这些受体在中国仓鼠卵巢细胞中表达时，未观察到这种效应。CGN的切片记录一致地表明，EtOH增加相位自发抑制性突触后电流（sIPSC）的频率，以及强直电流振幅和噪声。然而，对于乙醇是否直接作用于突触外受体或间接调节它们，即通过增加突触释放的GABA的溢出，缺乏共识。最近证明，α（6）亚基的氨基酸100的R至Q突变增加了EtOH对sIPSC和紧张性电流的作用。这些电生理学发现在我们手中是不可复制的。此外，研究表明，α（6）-R100 Q突变增强了远交Sprague-Dawley大鼠对EtOH运动损伤效应的敏感性，但在选择性饲养的对EtOH诱导的运动改变高度敏感的大鼠系（酒精非耐受大鼠）中未观察到这一点。我们的结论是，目前没有足够的证据确凿地支持直接增强突触外GABAA受体急性乙醇暴露在CGN。(c)2007爱思唯尔公司All rights reserved.
Cerebellar granule neurons (CGNs) receive inhibitory input from Golgi cells in the form of phasic and tonic currents that are mediated by postsynaptic and extrasynaptic gamma-aminobutyric acid type A (GABA(A)) receptors, respectively. Extrasynaptic receptors are thought to contain 040 subunits. Here, we review studies on ethanol (EtOH) modulation of these receptors, which have yielded contradictory results. Although studies with recombinant receptors expressed in Xenopus oocytes indicate that alpha(6)beta(3)delta receptors are potently enhanced by acute exposure to low ( >= 3 mM) EtOH concentrations, this effect was not observed when these receptors were expressed in Chinese hamster ovary cells. Slice recordings of CGNs have consistently shown that EtOH increases the frequency of phasic spontaneous inhibitory postsynaptic currents (sIPSCs), as well as the tonic current amplitude and noise. However, there is a lack of consensus as to whether EtOH directly acts on extrasynaptic receptors or modulates them indirectly; that is, via an increase in spillover of synaptically released GABA. It was recently demonstrated that an R to Q mutation of amino acid 100 of the alpha(6) subunit increases the effect of EtOH on both sIPSCs and tonic current. These electrophysiological findings have not been reproducible in our hands. Moreover, it was shown the alpha(6)-R100Q mutation enhances sensitivity to the motor-impairing effects of EtOH in outbred Sprague-Dawley rats, but this was not observed in a line of rats selectively bred for high sensitivity to EtOH-induced motor alterations (Alcohol Non-Tolerant rats). We conclude that currently there is insufficient evidence conclusively supporting a direct potentiation of extrasynaptic GABAA receptors following acute EtOH exposure in CGNs. (c) 2007 Elsevier Inc. All rights reserved.