GABA and its receptors in epilepsy.
GABA and its receptors in epilepsy.
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DOI：
10.1007/978-1-4757-6376-8_7
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发表时间：
2004
影响因子：
--
通讯作者：
G. Sperk;S. Furtinger;C. Schwarzer;S. Pirker
中科院分区：
文献类型：
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作者：
G. Sperk;S. Furtinger;C. Schwarzer;S. Pirker
γ-氨基丁酸（GABA）是哺乳动物脑内主要的抑制性神经递质。它通过2类受体发挥作用，即对通道进行配体操作的GABA A受体和G蛋白偶联代谢型GABA B受体。通过基因突变或应用GABA受体拮抗剂损害GABA能传递诱导癫痫发作，而增强GABA能传递的药物用于抗癫痫治疗。在动物癫痫模型和颞叶癫痫患者的组织中，观察到海马GABA神经元亚群的丢失。另一方面，电生理学和神经化学研究表明，在某些突触GABA能传递的代偿性增加。此外，在GABAA受体水平，神经变性诱导的受体损失伴随着齿状回和海马结构其他部分中受体亚单位表达的显著改变，表明GABAA受体的生理学和药理学改变。这些机制可能与癫痫发作诱导、内源性保护机制增强和抗癫痫药物治疗抵抗高度相关。其他研究表明GABA受体在失神发作中的作用。突触前GABA受体抑制神经递质的释放。取决于该作用是在GABA能神经元还是在谷氨酸能神经元中发挥，可能有抗惊厥或促惊厥作用。γ-氨基丁酸（GABA）是哺乳动物脑中的主要抑制性神经递质。1它通过两类受体发挥作用，即作为配体操作离子通道的GABA A受体和G-蛋白偶联代谢型GABA B受体（综述见参考文献2）。GABA能神经元广泛分布，在所有神经元功能的加工和整合中发挥重要作用。因此，荷包牡丹碱、戊四氮或印防己毒素阻断快速抑制性GABA A受体导致实验动物严重运动性癫痫发作并不奇怪。3，4因此，GABA能系统功能障碍可能在急性癫痫发作的传播和癫痫综合征的表现中起重要作用。事实上，缺乏谷氨酸脱羧酶（GAD）或GABAA受体某些亚基的突变小鼠容易发生自发性癫痫。5 - 7同样，具有GAD-67自身抗体的患者患有所谓的僵硬人综合征，并且通常也会发生癫痫。8，9最严重和最常见的癫痫综合征之一是颞叶癫痫（TLE）。它是由长期的热性惊厥或癫痫持续状态引发的，并且需要数年甚至超过十年才表现出来。10，11在临床上，TLE难以治疗，并且患者经常对药物治疗产生耐药性。12反复和长期的癫痫发作也可能导致在颞叶中观察到的严重神经元损伤，特别是在海马、内嗅皮层、杏仁核和其他脑区。13，14最典型的特征之一是海马体中主要神经元的严重损失，特别是在CA 1和CM 3区，而齿状回的颗粒细胞以及CA 2区和下托的锥体神经元相对较少。10，由于其临床相关性和TLE在长时间的“沉默”期内发展的特征，在过去的几十年中，人们做出了相当大的努力来研究其病理生理学。动物模型模仿TLE的不同方面，如诱导...
γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It acts through 2 classes of receptors, GABAAreceptors that are ligand-operated on channels and the G-protein-coupled metabotropic GABABreceptors. Impairment of GABAergic transmission by genetic mutations or application of GABA receptor antagonists induces epileptic seizures, whereas drugs augmenting GABAergic transmission are used for antiepileptic therapy. In animal epilepsy models and in tissue from patients with temporal lobe epilepsy, loss in subsets of hippocampal GABA neurons is observed. On the other hand, electrophysiological and neurochemical studies indicate a compensatory increase in GABAergic transmission at certain synapses. Also, at the level of the GABAAreceptor, neurodegeneration-induced loss in receptors is accompanied by markedly altered expression of receptor subunits in the dentate gyrus and other parts of the hippocampal formation, indicating altered physiology and pharmacology of GABAAreceptors. Such mechanisms may be highly relevant for seizure induction, augmentation of endogenous protective mechanisms, and resistance to antiepileptic drug therapy. Other studies suggest a role of GABABreceptors in absence seizures. Presynaptic GABABreceptors suppress neurotransmitter release. Depending on whether this action is exerted in GABAergic or glutamatergic neurons, there may be anticonvulsant or proconvulsant actions.γ—aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain.1It acts through 2 classes of receptors, GABAAreceptors that are ligand-operated ion channels and the G-protein-coupled metabotropic GABABreceptors (for review see ref. 2). GABAergic neurons are ubiquitously distributed and encompass a fundamental role in processing and integration of all neuronal functions. It is therefore not surprising that blockade of the fast inhibitory GABAAreceptors by bicuculline, pentylenetetrazol or picrotoxin causes severe motor seizures in experimental animals.3,4It has therefore been suggested that dysfunction of the GABAergic system may have a fundamental role in the propagation of acute seizures and in the manifestation of epilepsy syndromes. Indeed, mutant mice lacking the enzyme glutamate decarboxylase (GAD) or certain subunits of GABAAreceptors are prone to spontaneous epileptic seizures.5–7In the same way, patients with auto-antibodies to the enzyme GAD-67 suffer from the so called Stiff-man-syndrome, and often develop also epilepsy.8,9One of the most serious and frequent epilepsy syndromes is temporal lobe epilepsy (TLE). It is initiated by prolonged febrile seizures or status epilepticus, and takes years or even more than a decade until it is manifested.10,11In the clinic, TLE is difficult to treat, and patients frequently become resistant to drug therapy.12Repeated and prolonged seizures may also contribute to the severe neuronal damage observed in the temporal lobe, notably in the hippocampus, entorhinal cortex, amygdala and other brain areas.13,14One of the most typical features is the severe loss of principal neurons in the hippocampus proper, notably in sectors CA1 and CM3, whereas granule cells of the dentate gyrus, and pyramidal neurons of the sector CA2 and the subiculum, are relatively spared.10,15Because of its clinical relevance and the feature that TLE develops over a prolonged “silent” period, considerable effort has been made through the past decades to investigate its pathophysiology. Animal models mimicking different aspects of TLE, like the induction by …