Involvement of GABA-mediated inhibitory neuronal processes in seizure activity in rat hippocampal slices

本研究的主要目的是阐明γ-氨基丁酸（GABA）介导的抑制机制在癫痫发作活动产生中的作用。我们使用了一个体外癫痫模型，在该模型中，在对大鼠海马CA1区辐射层重复施加高频刺激（1秒，100赫兹）后，会诱导发作性活动样节律性放电（Ads）。我们之前报道过GABA_A受体拮抗剂双管碱抑制AD的产生，这表明GABA_A介导的抑制机制的激活可能是AD活性的必要条件。为了检验该模型是否可以作为颞叶癫痫的体外发作模型，我们检测了抗癫痫药物对该模型的影响。苯妥英和卡马西平对颞叶癫痫相关发作具有临床疗效，在其临床相关浓度下，可抑制AD的产生。另一方面，临床上对失神性癫痫有效但对颞叶癫痫无效的乙氧亚胺在其临床相关浓度下对AD的产生没有影响。这些发现提示我们的实验模型可以成为颞叶癫痫的实验性发作模型。此外，我们还记录了CA1区锥体神经元的细胞内电位。重复高频刺激CA1辐射层后，单次刺激诱导的gaba_a介导的抑制性突触后电位振幅增加，AD发生增强。因此，我们认为激活gaba_a介导的抑制过程对于颞叶癫痫的发作诱导是必要的，并提出了对癫痫发生的简单去抑制假说的修正。

The main purpose of our study is to clarify the involvement of γ-aminobutric acid (GABA)-mediated inhibitory mechanism in generation of seizure activity of epilepsy. We used an in vitro seizure model, in which ictal activity-like rhythmic afterdischarges (Ads) are developmentally induced following repetitive application of high-frequency stimuli (1 sec, 100 Hz) to the stratum radiatum of the CA1 region in rat hippocampal slices. We have previously reported that the GABA_A receptor antagonist bicuculline suppresses AD generation, suggesting that activation of GABA_A-mediated inhibitory mechanism may be necessary for ictal activity.In order to test whether this model can serve as an in vitro seizure model for temporal lobe epilepsy, we examined the effects of antiepileptic drugs on this model. Bath application of phenytoin and carbamazepine, which are clinically effective against seizures associated with temporal lobe epilepsy, suppressed AD generation at their clinically relevant concentrations. On the other hand, ethosuximide which is clinically effective against absence seizure but not against temporal lobe epilepsy had no effect on AD generation at its clinically relevant concentration. These findings suggest that our experimental model can become an experimental seizure model for temporal lobe epilepsy. In addition, we recorded intracellular potentials of pyramidal neurons in the CA1 region. Following repetitive high-frequency stimulation to the CA1 stratum radiatum, the amplitude of GABA_A-mediated inhibitory postsynaptic potentials induced by single stimuli increased in conjunction with enhancement in AD generation. Therefore we conclude that activation of GABA_A-mediated inhibitory processes is necessary for seizure induction of temporal lobe epilepsy, and propose a modification to the simple disinhibition hypothesis for epileptogenesis.