Bumanglag Argyle V, Sloviter Robert S
Departments of Pharmacology and Neurology, Graduate Program in Neuroscience, University of Arizona College of Medicine, Tucson, Arizona 85724, USA.
J Comp Neurol. 2008 Oct 20;510(6):561-80. doi: 10.1002/cne.21801.
Hippocampal epileptogenesis is hypothesized to involve secondary mechanisms triggered by initial brain injury. Chemoconvulsant-induced status epilepticus has been used to identify secondary epileptogenic mechanisms under the assumption that a seizure-free, preepileptic "latent period" exists that is long enough to accommodate delayed mechanisms. The latent period is difficult to assess experimentally because early spontaneous seizures may be caused or influenced by residual chemoconvulsant that masks the true duration of the epileptogenic process. To avoid the use of chemoconvulsants and determine the latency to hippocampal epileptogenesis and clinical epilepsy, we developed an electrical stimulation-based method to evoke hippocampal discharges in awake rats and produce hippocampal injury and hippocampal-onset epilepsy reliably. Continuous video monitoring and granule cell layer recording determined whether hippocampal epileptogenesis develops immediately or long after injury. Bilateral perforant pathway stimulation for 3 hours evoked granule cell epileptiform discharges and convulsive status epilepticus with minimal lethality. Spontaneous stage 3-5 behavioral seizures reliably developed within 3 days poststimulation, and all 72 spontaneous behavioral seizures recorded in 10 animals were preceded by spontaneous granule cell epileptiform discharges. Histological analysis confirmed a reproducible pattern of limited hippocampal and extrahippocampal injury, including an extensive bilateral loss of hilar neurons throughout the hippocampal longitudinal axis. These results indicate that hippocampal epileptogenesis after convulsive status epilepticus is an immediate network defect coincident with neuron loss or other early changes. We hypothesize that the latent period is directly related and inversely proportional to the extent of neuron loss in brain regions involved in seizure initiation, spread, and clinical expression.
海马体癫痫发生被假定涉及由初始脑损伤触发的继发性机制。化学惊厥剂诱导的癫痫持续状态已被用于识别继发性癫痫发生机制，其假设是存在一个无癫痫发作的癫痫前期“潜伏期”，该潜伏期足够长以适应延迟机制。潜伏期很难通过实验评估，因为早期的自发性癫痫发作可能由残留的化学惊厥剂引起或受其影响，从而掩盖了癫痫发生过程的真实持续时间。为了避免使用化学惊厥剂并确定海马体癫痫发生和临床癫痫的潜伏期，我们开发了一种基于电刺激的方法，以在清醒大鼠中诱发海马体放电，并可靠地产生海马体损伤和海马体起始癫痫。连续视频监测和颗粒细胞层记录确定了海马体癫痫发生是在损伤后立即出现还是在很久之后出现。双侧穿通通路刺激3小时可诱发颗粒细胞癫痫样放电和惊厥性癫痫持续状态，且致死率极低。刺激后3天内可靠地出现了自发的3-5期行为性癫痫发作，并且在10只动物中记录的所有72次自发行为性癫痫发作之前均有自发的颗粒细胞癫痫样放电。组织学分析证实了海马体和海马体外损伤有限的可重复模式，包括整个海马体纵轴上双侧海马门区神经元广泛缺失。这些结果表明，惊厥性癫痫持续状态后的海马体癫痫发生是一种与神经元丢失或其他早期变化同时出现的即时网络缺陷。我们假设潜伏期与癫痫发作起始传播和临床表现所涉及脑区的神经元丢失程度直接相关且成反比。
