Molecular Neuroanatomy and Pathogenesis Unit, Neurological Institute C. Besta, via Temolo 4, 20126 Milano, Italy.
Brain. 2011 Oct;134(Pt 10):2828-43. doi: 10.1093/brain/awr045. Epub 2011 Apr 10.
We have generated an experimental 'double-hit' model of chronic epilepsy to recapitulate the co-existence of abnormal cortical structure and frequently recurrent seizures as observed in human focal cortical dysplasia. We induced cortical malformations by exposing rats prenatally to methylazoxymethanol acetate and triggered status epilepticus and recurrent seizures in adult methylazoxymethanol acetate rats with pilocarpine. We studied the course of epilepsy and the long-term morphologic and molecular changes induced by the occurrence of status epilepticus and subsequent chronic epilepsy in the malformed methylazoxymethanol acetate exposed brain. Behavioural and electroencephalographic analyses showed that methylazoxymethanol acetate pilocarpine rats develop more severe epilepsy than naïve rats. Morphologic and molecular analyses demonstrated that status epilepticus and subsequent seizures, but not pilocarpine treatment per se, was capable of affecting both cortical architectural and N-methyl-D-aspartate receptor abnormalities induced by methylazoxymethanol acetate. In particular, cortical thickness was further decreased and N-methyl-D-aspartate regulatory subunits were recruited at the postsynaptic membrane. In addition, methylazoxymethanol acetate pilocarpine rats showed abnormally large cortical pyramidal neurons with neurofilament over-expression. These neurons bear similarities to the hypertrophic/dysmorphic pyramidal neurons observed in acquired human focal cortical dysplasia. These data show that status epilepticus sets in motion a pathological process capable of significantly changing the cellular and molecular features of pre-existing experimental cortical malformations. They suggest that seizure recurrence in human focal cortical dysplasia might be an additional factor in establishing a pathological circuitry that favours chronic neuronal hyperexcitability.
我们建立了一个实验性的“双打击”慢性癫痫模型，以重现人类局灶性皮质发育不良中观察到的异常皮质结构和频繁复发癫痫的共存现象。我们通过在产前暴露于甲基乙基亚硝脲乙酸（Methylazoxymethanol Acetate，MAM）的方式诱导皮质畸形，并在成年 MAM 暴露的大鼠中使用匹鲁卡品（Pilocarpine）引发癫痫持续状态和反复癫痫发作。我们研究了癫痫的发展过程，以及癫痫持续状态和随后的慢性癫痫发作在畸形 MAM 暴露脑内引发的长期形态和分子变化。行为和脑电图分析表明，MAM 匹鲁卡品大鼠比对照大鼠发展出更严重的癫痫。形态和分子分析表明，癫痫持续状态和随后的癫痫发作，而不仅仅是匹鲁卡品治疗本身，能够影响 MAM 诱导的皮质结构和 N-甲基-D-天冬氨酸受体异常。特别是，皮质厚度进一步降低，N-甲基-D-天冬氨酸调节亚基被募集到突触后膜。此外，MAM 匹鲁卡品大鼠表现出皮质锥体神经元异常增大，伴有神经丝过度表达。这些神经元与在获得性人类局灶性皮质发育不良中观察到的肥大/畸形锥体神经元相似。这些数据表明，癫痫持续状态引发了一个病理过程，能够显著改变预先存在的实验性皮质畸形的细胞和分子特征。它们提示，人类局灶性皮质发育不良中的癫痫复发可能是建立有利于慢性神经元过度兴奋的病理回路的另一个因素。
