SEIZURES IN HIPPOCAMPI OF EPILEPTIC CHILDREN

人类海马区癫痫是最难治疗的癫痫之一。 需要控制的症状。这些难治性且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氏角 神经元丢失和异常轴突可塑性的证据，称为 海马区硬化(HS)。HS的病因尚不清楚，而且确实如此 同样不清楚HS是否是慢性前列腺炎的病理生理基础 癫痫或多次癫痫发作的病理后果。独一无二的 海马体的发育特征是出生后的神经发生， 颗粒细胞的迁移和轴突形成。GC是父代 苔藓纤维(Mf)神经元是主要的异常出芽神经元之一。 HS中的轴突系统。我们最近有了一个独特的机会来研究 手术切除癫痫儿童的海马区以辨别 与癫痫发作和出生后相关的病理变化的演变 GC成熟。初步结果显示有异常的MF发芽的证据 在出生后GC发育的时候。中频纤维的大小和 老年癫痫患者的发作量增加，提示其成熟 这些轴突。癫痫发作相关区下神经元丢失。 所有癫痫儿童，但在2岁后发现更大的神经元丢失 几年后，大脑皮层细胞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海马体，并将 确定以下具体目标。L)决定进步性 海马区的病理改变可能是脑性痴呆的病因 成人HS。我们的两个假设是成人HS要么是结果 进行性癫痫相关的病理改变，或者它是 一些与结构损伤有关的严重的围产期侮辱。2) 测定出生后海马区发育的时间进程。我们会 寻找与神经发生相关的蛋白质在体内的表达， 迁移和轴突生长锥体的形成。我们的假设是 出生后的肺门细胞和GC将差异表达这些蛋白 与胎儿期形成的剩余海马体相比。3) 测定神经营养因子的出生后差异表达 (NTF)在发育中的海马区。我们的假设是信使核糖核酸转录因子 癫痫患者海马区的表达发生改变，促进 并在出生后轴突发育期间维持异常萌发。年龄- 没有脑部病理证据的匹配尸检海马体将提供服务 作为对照。将对大鼠幼鼠进行平行的发育研究 为了确定出生后的海马体成熟是否与另一个有所不同 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 这一点将在未来的人类和动物实验中进行扩展以进行研究 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。最重要的组成部分是 培训将是获取研究技能，这些技能将补充我的 现有的神经外科临床知识和培训。这项研究 课程包含对基础神经科学毕业生的授课接触 课程，亲身实践接触分子的技术和理论 神经生物学、教学和资深神经科学家的密切监督。 我们的目标是充分的研究、培训和接触，以成为一名 熟悉基础研究的独立临床调查员适用于 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.