Bureau M, Laschet J, Minier F, Chauvel P
Laboratoire de Neurosciences, Université de Rennes 1, France.
Rev Neurol (Paris). 1997;153 Suppl 1:S46-54.
The gamma-aminobutyric acid (GABA) is one of the most important inhibitory transmitter in the CNS. When GABA is released in the synaptic cleft, it can act on two types of receptors, type A (GABAA-R) and type B. The GABAA-R is an ionotropic receptor whose subunits form a chloride channel. It contains specific binding sites at least for GABA, benzodiazepines, picrotoxin, barbiturates, anesthetic steroids, divalent cations such as Zn2+ and other compounds. Neurotransmitters and neuropeptides that regulate intracellular second messengers may modulate the responses of GABAA-R in the post-synaptic membrane and thus affect the synaptic plasticity. While consensus sites for several kinases are present on many subunit-subtypes, the functional consequences of these phosphorylations are unclear. However, the maintenance of normal GABA currents required the activity of a unique kinase specific for the GABAA-R. This intracellular regulation site might be involved in synaptic plasticity and considered as a site of vulnerability for epileptogenesis. The generation of epileptic discharge, synchronized burst firing and interictal spikes, can be subsequent to the alteration of GABAA-R function. A consequence of GABAergic disinhibition is the formation of new polysynaptic pathways leading to a network of neurons that were previously not connected. Cell loss and plasticity are currently observed in most patients with temporal lobe epilepsy. CA1 pyramidal cells are missing and mossy fibers of dentate granule cells project back through the granule cell layer to form recurrent terminals on granule cell dendrites. This mossy fiber sprouting leads to the destruction of most dentate hilar somatostatine interneurons. Nevertheless, local circuit neurons containing glutamic acid decarboxylase survive in this layer and in all regions of the sclerotic hippocampus. A decrease of the GABA release has been proposed as a basis for disinhibition temporal-lobe epilepsy is partially characterized by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters. A molecular reorganization of GABAA-R subunits has been suggested in the kindling model of temporal lobe epilepsy because the zinc released from abberantly sprouted mossy fiber terminals is responsible for a collapse of augmented inhibition by GABA. These results support the concept of a loss of inhibition in chronic epilepsy models and probably in human epilepsies.
γ-氨基丁酸（GABA）是中枢神经系统中最重要的抑制性神经递质之一。当GABA在突触间隙释放时，它可作用于两种类型的受体，即A型（GABAA-R）和B型。GABAA-R是一种离子型受体，其亚基形成一个氯离子通道。它至少含有针对GABA、苯二氮䓬类、印防己毒素、巴比妥类、麻醉性类固醇、二价阳离子如Zn2+以及其他化合物的特异性结合位点。调节细胞内第二信使的神经递质和神经肽可能会调节突触后膜上GABAA-R的反应，从而影响突触可塑性。虽然许多亚基亚型上存在几种激酶的共有位点，但这些磷酸化的功能后果尚不清楚。然而，正常GABA电流的维持需要一种对GABAA-R具有特异性的独特激酶的活性。这个细胞内调节位点可能参与突触可塑性，并被认为是癫痫发生的一个易损位点。癫痫放电、同步爆发式放电和发作间期棘波的产生可能继发于GABAA-R功能的改变。GABA能抑制解除的一个后果是形成新的多突触通路，导致先前未连接的神经元网络。目前在大多数颞叶癫痫患者中观察到细胞丢失和可塑性。CA1锥体细胞缺失，齿状颗粒细胞的苔藓纤维通过颗粒细胞层向后投射，在颗粒细胞树突上形成折返终末。这种苔藓纤维出芽导致大多数齿状门部生长抑素中间神经元被破坏。然而，含有谷氨酸脱羧酶的局部回路神经元在该层以及硬化海马体的所有区域中存活。有人提出GABA释放减少是抑制解除的基础，颞叶癫痫的部分特征是谷氨酸刺激的GABA释放丧失，这继发于GABA转运体数量的减少。在颞叶癫痫的点燃模型中，有人提出GABAA-R亚基发生了分子重组，因为异常出芽的苔藓纤维终末释放的锌导致GABA增强抑制作用的崩溃。这些结果支持了慢性癫痫模型以及可能在人类癫痫中存在抑制丧失的概念。
