SEIZURES IN HIPPOCAMPI OF EPILEPTIC CHILDREN

人类海马癫痫是最难治疗的癫痫之一 症状控制。 这些顽固的，往往是严重的癫痫发作， 与电生理过度兴奋相关的严重阿蒙角 神经元丢失和异常轴突可塑性的证据，称为 海马硬化（HS）。HS的病因尚不清楚， 同样不清楚HS是否是慢性炎症的病理生理学底物， 癫痫或多次癫痫发作的病理后果。一个独特 海马的发育特征是出生后的神经发生， 颗粒细胞（GC）的迁移和轴突形成。GC是父代 苔藓纤维（MF）神经元，一个主要的异常发芽 HS的轴突系统。我们最近有一个独特的机会来研究 手术切除癫痫儿童的前穹窿， 病理变化的演变，因为它们与癫痫发作和产后 GC成熟。初步结果显示异常MF发芽的证据 在出生后GC发育的时候。MF纤维的尺寸和 在老年癫痫患者中，扣结增加，表明 这些轴突癫痫发作相关的下区神经元丢失被发现， 所有癫痫儿童，但2岁后发现更多的神经元丢失 几年后，GC几乎完成了神经发生。这项建议是 旨在进一步研究癫痫儿童的癫痫， 确定以下具体目标。（一）确定渐进式 海马体的病理变化可能表明 成人HS我们的两个假设是，成年HS是结果， 进行性癫痫发作相关的病理变化，或者是由于 一些严重的围产期损伤与结构损伤有关。（二） 确定出生后海马发育的时间进程。我们将 寻找与神经发生相关的蛋白质的体内表达， 迁移和轴突生长锥形成。我们的假设是 出生后的肝门细胞和GC将差异表达这些蛋白质 而剩下的海马体是在产前形成的。第三章 确定神经营养因子的出生后差异表达 (NTF)在发育中的海马体中。我们的假设是mRNA NTF 癫痫海马中的表达发生改变，从而促进 并在出生后轴突发育期间维持异常发芽。年龄- 没有脑部病理学证据的匹配尸检结果 作为对照将在大鼠幼仔中进行平行发育研究 以确定出生后海马体的成熟是否与另一个 哺乳动物物种。这些关于癫痫儿童的研究形成了一个数据库 在未来的人类和动物实验中， HS的细胞机制和病理生理学。 加拿大国际开发署也是一种培训补助金。最重要的组成部分 培训将是在获得研究技能，将补充我的 神经外科现有的临床知识和培训。研究 该计划包含一个教学接触基础神经科学研究生 课程，动手技术和理论接触分子 神经生物学，教学和高级神经科学家的密切监督。 目标是足够的研究培训和接触，成为一个 熟悉基础研究的独立临床研究者， 临床癫痫相关问题。

Human hippocampal epilepsy is one of the most difficult epileptic syndromes to control. These intractable and often severe seizures are associated with electrophysiologic hyperexcitability, severe Ammon's horn neuron loss, and evidence of aberrant axonal plasticity, termed hippocampal sclerosis (HS). The etiology of HS is unknown, and it is likewise unclear if HS is the pathophysiologic substrate of chronic epilepsy or the pathologic consequence of multiple seizures. A unique developmental feature of the hippocampus is the postnatal neurogenesis, migration and axon formation of granule cells (GC). The GCs are the parent neurons for mossy fibers (MF), one of the principal aberrantly sprouted axon systems in HS. We recently have had the unique opportunity to study surgically resected hippocampi from epileptic children to discern the evolution of pathologic changes as they relate to seizures and postnatal GC maturation. Preliminary results show evidence of aberrant MF sprouting at the time of postnatal GC development. The size of the MF fibers and boutons increased in older seizure patients, suggesting maturation of these axons. Seizure associated regio inferior neuron loss was found in all epileptic children, but greater neuron loss was found after age 2 years, when the GCs had nearly completed neurogenesis. This proposal is designed to further study hippocampi from epileptic children and will determine the following specific aims. l) Determine the progressive pathologic changes in the hippocampus that might suggest an etiology of adult HS. Our two hypotheses are that adult HS is either the consequence of progressive seizure related pathologic changes or it is a result of some severe perinatal insult that is associated with structural damage. 2) Determine the time course of postnatal hippocampal development. We will look for the in vivo expression of proteins associated with neurogenesis, migration, and axon growth cone formation. Our hypothesis is that postnatal hilar cells and GCs will differentially express these proteins compared with the remaining hippocampus which forms prenatally. 3) Determine the postnatal differential expression of neurotrophic factors (NTF) in the developing hippocampus. Our hypothesis is that mRNA NTF expression is altered in epileptic hippocampi in a manner that promotes and maintains aberrant sprouting during postnatal axon development. Age- matched autopsy hippocampi without evidence of brain pathology will serve as controls. Parallel developmental studies will be performed in rat pups to determine if postnatal hippocampal maturation is different in another mammalian species. These studies on epileptic children form a data base that will be expanded upon in future human and animal experiments to study the cellular mechanisms and pathophysiology of HS. A CIDA is also a training grant. The most significant component of the training will be in acquiring research skills that will complement my existing clinical knowledge and training in Neurosurgery. The research program contains a didactic exposure to basic Neuroscience graduate courses, hands on technical and theoretical exposure to molecular neurobiology, teaching, and close supervision by senior neuroscientists. The goal is sufficient research training and exposure to become an independent clinical investigator familiar with basic research applied to clinical epilepsy related problems.