首页> 美国卫生研究院文献>Advances in Pharmacological Sciences >Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors
【2h】

Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors

机译:增强癫痫发作时强直GABAA抑制作用的增强:反向激动剂在突触外GABAA受体上的治疗价值

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务,本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文,但由于OA文献来源多样且变更频繁,仍可能出现获取不到、文献不完整或与标题不符等情况,如果获取不到我们将提供退款服务。请知悉。

摘要

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABAA receptors (eGABAAR) and augmented “tonic” GABAA inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABAAR gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABAARs in absence epilepsy.
机译:公认的是,神经元网络内GABA能抑制的减弱可导致超同步放电模式,这是惊厥性癫痫发作的典型细胞标志。但是,最近的发现强调,丘脑皮层回路中GABA能信号的病理增强是非惊厥性典型失神发作的必要条件。尤其是,在无癫痫病的一系列遗传和药理模型中,已经证明了丘脑皮质神经元中突触外GABAA受体(eGABAAR)的活化增强和“强直” GABAA抑制作用增强。此外,来自单基因小鼠模型(占星者/昏迷者)和斯特拉斯堡的多基因遗传性癫痫大鼠(GAERS)的证据表明,eGABAAR功能获得的潜在机制本质上是非神经元的,并且是由于GAT- 1个转运车。这些结果挑战了现有的理论,即在丘脑皮层回路中广泛缺乏GABA能的功能支持了典型的失神发作,并说明了星形胶质细胞在典型的失神癫痫病中的重要作用。此外,他们解释了为什么增强GABA受体功能的药理学剂会引发或加剧失神发作,并提示失神癫痫患者eGABAARs反向激动剂具有潜在的治疗作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号