Germano I M, Sperber E F
Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Neurosci Res. 1998 Feb 15;51(4):473-88. doi: 10.1002/(SICI)1097-4547(19980215)51:4<473::AID-JNR7>3.0.CO;2-9.
Recent clinical and laboratory data suggest that there is a link between neuronal migration disorders (NMD) and increased seizure threshold. To characterize an animal model with features similar to human NMD and to assess seizure susceptibility, NMD were induced in the rat at the time of neuroblastic division (PG15) and three other gestational ages (PG 13, PG14, PG16) by transplacental exposure to methylaxozymethanol (MAM, 25 mg/kg). Offspring pups were monitored for spontaneous and electrographic seizures. At postnatal day 14, randomly selected rat pups were sacrificed for histological examination. In other MAM-exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid. On histology, NMD were found in all PG 15 MAM-exposed rats, in comparison to 63% of PG 13, 70% of PG 14, 80% of PG16. Histological features included cortical laminar disorganization, ectopic neurons in the subcortical white matter and in cortical layer I, persistent granular layer, marginal glioneuronal heterotopia, and discrete areas of neuronal ectopia in the CA1 subfield of the hippocampus. Based on the severity of the neuronal migration abnormalities, rats were divided into three categories: severe, moderate, and mild. Severe and moderate NMD were only found in the PG 15 MAM-exposed rats. EEG recording in rats with NMD did not disclose spontaneous seizures; however, rats with severe NMD had higher slow wave activity compared to controls (P < .05). MAM-exposed rats with severe NMD were more susceptible to kainic-induced seizures compared to controls (P < .05). In rats with severe NMD, kainic acid-induced status epilepticus produced hippocampal damage in the CA3/4 region. These results demonstrate that MAM-induced NMD have histological and electrographic characteristics similar to human NMD. The severity of neuronal abnormality depends on the time of transplacental exposure as the most severe NMD were found after exposure to MAM at the time of neuroblastic division. The degree of NMD positively correlates with seizure susceptibility, since only rats with severe NMD have decreased seizure threshold. The occurrence of status epilepticus-induced hippocampal damage in pups with severe NMD suggests that the severely compromised hippocampus is less resistant to seizure-induced injury than the normal developing brain.
近期的临床和实验室数据表明，神经元迁移障碍（NMD）与癫痫发作阈值升高之间存在关联。为了建立一种具有与人类NMD相似特征的动物模型并评估癫痫易感性，在神经母细胞分裂期（PG15）以及其他三个胎龄（PG13、PG14、PG16）时，通过经胎盘暴露于甲基偶氮甲醇（MAM，25mg/kg）在大鼠中诱导NMD。对后代幼崽进行自发性和脑电图癫痫发作监测。在出生后第14天，随机选择大鼠幼崽进行组织学检查。在其他暴露于MAM的幼崽和对照组中，通过腹腔注射 kainic 酸诱导癫痫持续状态。组织学检查发现，所有暴露于PG15 MAM的大鼠均出现NMD，相比之下，PG13组为63%，PG14组为70%，PG16组为80%。组织学特征包括皮质层状结构紊乱、皮质下白质和皮质I层中的异位神经元、持续的颗粒层、边缘性神经胶质神经元异位以及海马CA1亚区离散的神经元异位区域。根据神经元迁移异常的严重程度，将大鼠分为三类：重度、中度和轻度。重度和中度NMD仅在暴露于PG15 MAM的大鼠中发现。NMD大鼠的脑电图记录未显示出自发性癫痫发作；然而，与对照组相比，重度NMD大鼠的慢波活动更高（P < 0.05）。与对照组相比，暴露于MAM且患有重度NMD的大鼠对 kainic 酸诱导的癫痫发作更敏感（P < 0.05）。在患有重度NMD的大鼠中，kainic 酸诱导的癫痫持续状态在CA3/4区域造成了海马损伤。这些结果表明，MAM诱导的NMD具有与人类NMD相似的组织学和脑电图特征。神经元异常的严重程度取决于经胎盘暴露的时间，因为在神经母细胞分裂期暴露于MAM后发现了最严重的NMD。NMD的程度与癫痫易感性呈正相关，因为只有患有重度NMD的大鼠癫痫发作阈值降低。重度NMD幼崽中癫痫持续状态诱导的海马损伤的发生表明，严重受损的海马比正常发育的大脑对癫痫发作诱导的损伤抵抗力更弱。
