Graduate Education in Biomedical Sciences Program, Morehouse School of Medicine, Atlanta, Georgia.
Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia.
Epilepsia. 2019 May;60(5):e52-e57. doi: 10.1111/epi.14723. Epub 2019 Apr 8.
Cryptogenic temporal lobe epilepsy develops in the absence of identified brain injuries, infections, or structural malformations, and in these cases, an unidentified pre-existing abnormality may initiate febrile seizures, hippocampal sclerosis, and epilepsy. Although a role for GABAergic dysfunction in epilepsy is intuitively obvious, no causal relationship has been established. In this study, hippocampal GABA neurons were targeted for selective elimination to determine whether a focal hippocampal GABAergic defect in an otherwise normal brain can initiate cryptogenic temporal lobe epilepsy with hippocampal sclerosis. We used Stable Substance P-saporin conjugate (SSP-saporin) to target rat hippocampal GABA neurons, which selectively and constitutively express the neurokinin-1 receptors that internalize this neurotoxin. Bilateral and longitudinally extensive intrahippocampal microinjections of SSP-saporin caused no obvious behavioral effects for several days. However, starting ~4 days postinjection, rats exhibited episodes of immobilization, abnormal flurries of "wet-dog" shakes, and brief focal motor seizures characterized by facial automatisms and forepaw clonus. These clinically subtle behaviors stopped after ~4 days. Convulsive status epilepticus did not develop, and no deaths occurred. Months later, chronically implanted rats exhibited spontaneous focal motor seizures and extreme hippocampal sclerosis. These data suggest that hippocampal GABAergic dysfunction is epileptogenic and can produce the defining features of cryptogenic temporal lobe epilepsy.
隐源性颞叶癫痫是在没有明确的脑损伤、感染或结构畸形的情况下发展的，在这些情况下，未明确定义的先前存在的异常可能会引发热性惊厥、海马硬化和癫痫。尽管 GABA 能功能障碍在癫痫中的作用是直观明显的，但尚未建立因果关系。在这项研究中，海马 GABA 神经元被靶向选择性消除，以确定在其他正常大脑中是否存在局灶性海马 GABA 能缺陷，是否可以引发伴有海马硬化的隐源性颞叶癫痫。我们使用稳定的神经激肽-1 受体配体-蓖麻毒素结合物（SSP-saporin）来靶向大鼠海马 GABA 神经元，这些神经元选择性和组成性地表达内吞这种神经毒素的神经激肽-1 受体。双侧和纵向广泛的海马内微注射 SSP-saporin 在数天内不会引起明显的行为效应。然而，从注射后约 4 天开始，大鼠出现了固定不动、异常的“湿狗”抖动和短暂的局灶性运动性癫痫发作，表现为面部自动症和前爪阵挛。这些临床轻微的行为在 4 天后停止。没有发展为癫痫持续状态，也没有死亡。数月后，慢性植入的大鼠表现出自发性局灶性运动性癫痫发作和极度的海马硬化。这些数据表明，海马 GABA 能功能障碍具有致痫性，可以产生隐源性颞叶癫痫的特征性表现。
