Department of Pediatrics, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
Department of Pediatrics, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
Exp Neurol. 2024 Jun;376:114759. doi: 10.1016/j.expneurol.2024.114759. Epub 2024 Mar 20.
Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12-15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility. Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8. In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls. These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.
皮质发育畸形（MCDs）是胎儿期神经元迁移过程异常引起的，是婴儿期难治性癫痫的主要原因。然而，MCD 中的过度兴奋或癫痫发生的时间仍不清楚。为了确定在婴儿期（P12-15）表现出更高癫痫易感性的 MCD 大鼠模型的大脑早期发育变化，我们分析了新生期 MCD 模型大鼠的大脑病理变化，并测试了 NMDA 诱导的癫痫易感性。给怀孕的大鼠注射两次剂量的甲基偶氮甲烷乙酸盐（MAM，15mg/kg，腹腔注射）诱导 MCD，而对照组给予生理盐水。通过对出生后第 1、5 和 8 天（P）进行磁共振成像（MRI）测量后代的皮质发育。在 P8 时，一些大鼠被处死用于免疫荧光、高尔基染色和 Western 分析。在另一组大鼠中，在 P8 时用 NMDA（5mg/kg 腹腔注射）注射后监测 90 分钟痉挛的数量和发作潜伏期。在 MCD 大鼠中，体内 MR 成像显示出生后第 1 天大脑体积更小，皮质更薄（p<0.001）。高尔基染色和免疫荧光显示异常的神经元迁移，在 P8 时神经元细胞群体数量减少，树突分支减少。此外，MCD 大鼠 NMDA 受体和 AMPAR4 的表达显著减少，而 AMPAR3 的表达增加（p<0.05）。尽管 MCD 大鼠和对照组之间的癫痫发作潜伏期没有差异，但 MCD 大鼠的存活时间明显长于对照组。这些结果提供了对 MCD 大鼠模型皮质早期发育变化的深入了解，并表明不成熟大脑中延迟和异常的神经元发育与 NMDA 诱导的兴奋性毒性损伤反应迟钝有关。这些发育变化可能与 MCD 或产前脑损伤患者癫痫的突然发作有关。
