Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus
Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus
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DOI：
10.1523/jneurosci.4944-04.2005
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发表时间：
2005-08-24
影响因子：
5.3
通讯作者：
Wasterlain, CG
中科院分区：
文献类型：
--
作者：
Naylor, DE;Liu, HT;Wasterlain, CG
在癫痫持续状态（SE）期间，gaba能机制失效，癫痫发作变得自我维持和耐药。在锂-匹罗卡品诱导的SE过程中，我们对齿状回颗粒细胞突触后GABA(A)受体的研究表明，微型IPSCs （mIPSCs）的振幅降低。解剖学研究表明，GABA(a)受体的β 2/ β 3和γ 2亚基与突触前标记物突触体素的共定位减少，而这些亚基在齿状颗粒细胞和其他海马神经元内部的比例增加。与突触性mIPSCs不同，突触外GABA(A)强直电流的振幅在SE期间增强。数学模型表明，SE的改变反映了功能性突触后GABA(a)受体数量的减少。它还表明，在SE期间细胞外[GABA]的增加可以解释强直电流的变化，并可以影响突触后受体动力学，失去对脉冲的抑制。GABA暴露模拟SE对颗粒细胞中mIPSC和强直GABA(A)电流振幅的影响，与模型预测一致。这些结果为SE起始的抑制性丧失和苯二氮卓类药物耐药提供了一种潜在的机制，即可用功能性GABA(a)突触后受体的减少。针对SE的新疗法可能旨在预防或逆转这些损失。
During status epilepticus ( SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithium-pilocarpine-induced SE, our studies of postsynaptic GABA(A) receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the beta 2/beta 3 and gamma 2 subunits of GABA(A) receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE. Unlike synaptic mIPSCs, the amplitude of extrasynaptic GABA(A) tonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA(A) receptors. It also suggests that increases in extracellular [GABA] during SE can account for the tonic current changes and can affect postsynaptic receptor kinetics with a loss of paired-pulse inhibition. GABA exposure mimics the effects of SE on mIPSC and tonic GABA(A) current amplitudes in granule cells, consistent with the model predictions. These results provide a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines, as a reduction of available functional GABA(A) postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.