Low-frequency electrical stimulation (LFES) of the brain is one of the promising methods for helping patients with pharmacoresistant epilepsy. However, the mechanism of the antiepileptic effect of LFES is still unclear. We applied electrophysiological and pharmacological tools and mathematical modeling to investigate it. Using the 4-aminopyridine (4-AP) model of epileptiform activity in juvenile rat brain slices, we found that LFES increased the interval between ictal discharges (IDs) in the entorhinal cortex. The blockade of GABAA, GABAB, AMPA, or NMDA synaptic receptors strongly affected the characteristics of epileptiform discharges in slices. However, only under the blockade of GABAB receptors, LFES becomes entirely ineffective, indicating that the activation of GABAB receptors underlies the main LFES antiepileptic effect. Further experiments allowed us to suggest that LFES activates mostly presynaptic GABAB receptors, which decrease the probability of glutamate release. In line with this hypothesis is the following data: 1) LFES reduces the short-term synaptic depression of excitatory postsynaptic currents similar to the agonist of GABAB receptors SKF-97541; 2) the blockade of excitatory amino acid transporters diminishes the antiepileptic effect of LFES; 3) modeling of the effects of LFES on the probability of glutamate release with a previously proposed mathematical model of epileptiform activity Epileptor-2 also shows the increase of the interval between IDs. Our findings point out a crucial role of presynaptic GABAB receptors in the antiepileptic effect of LFES in the 4-AP model in juvenile rat brain slices.

中文翻译：

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突触前 GABAB 受体是低频电刺激在年轻大鼠脑切片癫痫 4-氨基吡啶模型中抗癫痫作用的基础

大脑的低频电刺激 (LFES) 是治疗药物耐药性癫痫患者的有前途的方法之一。然而，LFES的抗癫痫作用机制尚不清楚。我们应用电生理学和药理学工具以及数学模型对其进行了研究。使用 4-氨基吡啶 (4-AP) 幼鼠脑切片癫痫样活动模型，我们发现 LFES 增加了内嗅皮层中发作放电 (ID) 的间隔。GABAA、GABAB、AMPA 或 NMDA 突触受体的阻断强烈影响了切片中癫痫样放电的特征。然而，仅在 GABAB 受体的阻断下，LFES 变得完全无效，表明 GABAB 受体的激活是主要的 LFES 抗癫痫作用的基础。进一步的实验使我们能够表明 LFES 主要激活突触前 GABAB 受体，这降低了谷氨酸释放的可能性。与此假设一致的是以下数据：1) LFES 减少了兴奋性突触后电流的短期突触抑制，类似于 GABAB 受体 SKF-97541 的激动剂；2）兴奋性氨基酸转运蛋白的阻断减弱了LFES的抗癫痫作用；3) 用先前提出的癫痫样活动数学模型对 LFES 对谷氨酸盐释放概率的影响进行建模。 Epileptor-2 也显示 ID 之间的间隔增加。我们的研究结果指出突触前 GABAB 受体在 LFES 在幼年大鼠脑切片 4-AP 模型中的抗癫痫作用中的关键作用。