Introduction. Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Temporal lobe epilepsy (TLE) is the most common and often drug-resistant type of epilepsies in the adult and aging populations and has greatly diverse in etiologies and electro-clinical manifestations. Kindling through repeated brief stimulation of limbic structures has long been used as a model of TLE. While classic kindling in a few weeks does not induce spontaneous recurrent seizures (SRS), extended kindling is able to induce SRS in several animal species. The SRS induction by extended kindling is generally not associated with gross brain injury, but rather a loss of subgroups of GABAergic interneurons in the hippocampal hilar region. The lack of observed gross brain injury in extended kindled animals is different from post status epilepticus models in which SRS emergence is accompanied with pronounced brain damage. As such the extended kindling model may help explore epileptogenesis in the absence of major brain pathology as is seen in many patients with TLE. To data, there is limited insight about EEG characteristics of SRS in rodent models of extended kindling. We therefore attempted to provide more information in this area using a mouse model of extended hippocampal kindling (Song et al., 2018; Liu et al., 2019; Frontier Pharmacology).

Methods. Male C57 black mice ages 11–13 months were operated to implant intracranial electrodes. Each mouse was implanted with two pairs of bipolar electrodes, one in the hippocampal CA3 for kindling stimulation and local recordings and another in contralateral/ipsilateral hippocampal CA3, dorsomedial thalamus, parietal cortex or entorhinal cortex. Hippocampal kindling (60 Hz for 2 sec) was applied twice daily, and SRS were detected by 24-hour EEG-video monitoring. Age-match mice that received similar electrode implantation and twice daily handling manipulation but not kindling were used as controls. Brain histological examinations were performed in a subset of mice to verify the location of implanted electrodes and to examine potential gross brain lesion.

Results. (1) SRS were observed from 47 mice following 80–140 kindling stimulation; no spontaneous seizure was detected in 12 control mice. (2) SRS remained detectable in individual mice up to 4 months after termination of the kindling stimulation. SRS incidences varied in a range of 2–14 events per day but inter-SRS intervals were ≤2 hours for about 65% of SRS events. (3) Most of SRS were featured with EEG ictal discharges and concurrent motor seizures at the Racine scale 3–5. SRS that presented EEG ictal discharges without or with concurrent motor behaviors at the Racine scale 1–2 were also noticeable, particularly in mice with implanted electrode in the dorsomedial thalamus. (4) In ≥1500 SRS events examined, nearly all EEG ictal discharges presented low-voltage signals at onset and such ictal onset appeared to concur in the kindled CA3 and unkindled site despite the latter targeted to different brain structures. (5) CA3 and cortical EEG ictal discharges were not substantially affected by intra-peritoneal injection of lorazepam (a benzodiazepine positive GABAa receptor modulator) but concurrent severe motor seizures were greatly suppressed.

Summary. We suggest that epileptogenic network activity encompassing multiple forebrain areas may be responsible for SRS initiation in the mouse model of extended hippocampal kindling. Subcortical structures involving the dorsomedial thalamic circuitry may play an important role in manifestation and/or control of severe motor seizures in this model.

Support. EpLink – The Epilepsy Research Program of the Ontario Brain Institute and Natural Sciences and Engineering Research Council of Canada.

简介. 癫痫是一种疾病，其特征是具有产生癫痫发作的持久倾向以及这种情况的神经生物学、认知、心理和社会后果。颞叶癫痫 (TLE) 是成人和老年人群中最常见且通常具有耐药性的癫痫类型，其病因和电-临床表现差异很大。通过反复短暂刺激边缘结构来点燃长期以来一直被用作 TLE 的模型。虽然几周内的经典点燃不会诱发自发性复发性癫痫 (SRS)，但延长点燃能够在几种动物物种中诱发 SRS。延长点燃引起的 SRS 诱导通常与严重的脑损伤无关，而是与海马门区中 GABA 能中间神经元亚群的丢失有关。在长时间点燃的动物中没有观察到严重的脑损伤与癫痫持续状态后模型不同，其中 SRS 出现伴随着明显的脑损伤。因此，扩展点燃模型可能有助于在没有主要脑病理学的情况下探索癫痫发生，正如许多 TLE 患者所见。对于数据，在啮齿动物扩展点燃模型中，对 SRS 的 EEG 特征的了解有限。因此，我们尝试使用扩展海马点燃的小鼠模型提供该领域的更多信息（Song 等人，2018 年；Liu 等人，2019 年；Frontier Pharmacology）。因此，扩展点燃模型可能有助于在没有主要脑病理学的情况下探索癫痫发生，正如许多 TLE 患者所见。对于数据，在啮齿动物扩展点燃模型中，对 SRS 的 EEG 特征的了解有限。因此，我们尝试使用扩展海马点燃的小鼠模型提供该领域的更多信息（Song 等人，2018 年；Liu 等人，2019 年；Frontier Pharmacology）。因此，扩展点燃模型可能有助于在没有主要脑病理学的情况下探索癫痫发生，正如许多 TLE 患者所见。对于数据，在啮齿动物扩展点燃模型中，对 SRS 的 EEG 特征的了解有限。因此，我们尝试使用扩展海马点燃的小鼠模型提供该领域的更多信息（Song 等人，2018 年；Liu 等人，2019 年；Frontier Pharmacology）。

方法。对 11-13 个月大的雄性 C57 黑色小鼠进行手术以植入颅内电极。每只小鼠都植入了两对双极电极，一个在海马 CA3 中用于点燃刺激和局部记录，另一个在对侧/同侧海马 CA3、背内侧丘脑、顶叶皮层或内嗅皮层中。每天两次使用海马点燃（60 Hz，持续 2 秒），并通过 24 小时 EEG 视频监测检测 SRS。接受类似电极植入和每天两次处理操作但不点燃的年龄匹配小鼠用作对照。在一组小鼠中进行了脑组织学检查，以验证植入电极的位置并检查潜在的脑损伤。

结果。(1) 47 只小鼠在 80-140 次点燃刺激后观察到 SRS；在 12 只对照小鼠中未检测到自发性癫痫发作。(2) 在点燃刺激终止后 4 个月内，SRS 在单个小鼠中仍可检测到。SRS 发生率在每天 2-14 次事件的范围内变化，但大约 65% 的 SRS 事件的 SRS 间间隔≤2 小时。(3) 大多数 SRS 的特征是脑电图发作性放电和同时发生的拉辛评分 3-5 的运动性癫痫发作。在 Racine 等级 1-2 中呈现 EEG 发作放电而没有或有并发运动行为的 SRS 也很明显，特别是在背内侧丘脑中植入电极的小鼠中。(4) 在检查的≥1500 个 SRS 事件中，几乎所有的脑电图发作放电在开始时都呈现低电压信号，这种发作似乎在点燃的 CA3 和未点燃的部位同时发生，尽管后者针对不同的大脑结构。(5) CA3 和皮质脑电图发作放电不受腹膜内注射劳拉西泮（一种苯二氮卓阳性 GABAa 受体调节剂）的显着影响，但同时发生的严重运动性癫痫发作受到极大抑制。

总结。我们建议包含多个前脑区域的致癫痫网络活动可能是扩展海马点燃小鼠模型中 SRS 启动的原因。在该模型中，涉及背内侧丘脑回路的皮层下结构可能在严重运动癫痫的表现和/或控制中发挥重要作用。

支持。EpLink – 安大略脑研究所和加拿大自然科学与工程研究委员会的癫痫研究计划。