Pathophysiology of Developing Dysplastic Human Cortex

描述（由申请人提供）：癫痫是一种常见的神经系统疾病，大约25%的儿童有医学难治性癫痫发作。在接受神经外科手术的耐药癫痫患儿中，皮质发育不良（CD）是最常见的病因。本研究的重点是确定小儿癫痫手术患者的癫痫发生机制。人类手术组织的使用是重要的，因为CD的动物模型不能完全复制人类的组织病理学，特别是异常的巨细胞神经元和球囊细胞。此外，该建议具有转化目的，将开发新的治疗儿童CD的方法。我们之前的研究确定了CD患者大脑皮层中正常和异常细胞的特征。这些研究发现MRI体积、神经元密度和电生理特性的变化类似于未成熟发育的皮层。基于这些发现，我们提出了大脑发育异常假说，该假说认为CD的组织病理学代表了正常的发育过程，如分子层和亚板细胞的凋亡以及突触成熟被减慢或停止，这与灰质中间层中晚出生的锥体神经元数量增加有关。我们认为，随着发育的延迟，异位位置的CD细胞，如分子层和皮层下过渡区（STZ），参与了癫痫发作的产生。此外，CD组织中的一些正常和异常细胞具有不成熟的突触特征，这是癫痫前的。这些假设将通过：1)检查神经元在分子层和STZ的形态和电生理特性来验证；2)使用双补丁记录检查正常和异常神经元对之间的突触相互作用；3)检测影响GABAA受体和氯离子转运体的药物组合、GABAB受体和mTOR通路（雷帕霉素）对CD患者突触活性和诱导癫痫样放电的急性影响。这些研究具有重要意义，因为它们阐明了乳糜泻患者发病和癫痫发生的操作机制，从而更好地确定癫痫发作的原因并开发治疗方法。

DESCRIPTION (provided by applicant): Epilepsy is a frequent neurological condition, and approximately 25% of children have medically refractory seizures. In children with pharmacoresistant epilepsy undergoing neurosurgery, cortical dysplasia (CD) is the most frequent etiology. This proposal focuses on identifying mechanisms of epileptogenesis in pediatric epilepsy surgery patients with CD. The use of human surgical tissue is important because animal models of CD do not fully replicate the histopathology seen in humans, especially abnormal cytomegalic neurons and balloon cells. Furthermore, this proposal has a translational aim that will develop new treatments for children with CD. Our previous studies identified the characteristics of normal and abnormal cells in the cerebral cortex of patients with CD. These studies found changes in MRI volumes, neuronal densities, and electrophysiological properties that resembled immature developing cortex. Based on these findings we introduced the Dysmature Cerebral Developmental Hypothesis, that proposes that the histopathology of CD represents tissue in which normal developmental processes, such as apoptosis of cells in the molecular layer and subplate and synaptic maturation are slowed or stopped in association with increased numbers of late born pyramidal neurons in the intermediate layers of the gray matter. We propose that with delayed development, CD cells in ectopic locations, such as the molecular layer and the subcortical transition zone (STZ), participate in seizure generation. In addition, some of the normal and abnormal cells in CD tissue have immature synaptic features that are pro-epileptic. These hypotheses will be tested by: 1) Examining the morphological and electrophysiological properties of neurons in the molecular layer and STZ; 2) Examining synaptic interactions between pairs of normal and abnormal neurons using dual patch recordings and; 3) Examining the acute effects of drug combinations that affect GABAA receptors and chloride transporters, GABAB receptors, and the mTOR pathway (rapamycin) on synaptic activity and induced epileptiform discharges in CD cases. These studies are significant because they elucidate operational mechanisms of pathogenesis and epileptogenesis in patients with CD to better define causes of the seizures and to develop treatments.