Pathophysiology of Developing Dysplastic Human Cortex

描述(申请人提供)：癫痫是一种常见的神经疾病，大约25%的儿童有医学上难治性癫痫发作。在接受神经外科手术的耐药癫痫儿童中，皮质发育不良(CD)是最常见的病因。这项建议侧重于确定儿童癫痫手术后CD患者的癫痫发生机制。使用人类手术组织很重要，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气球细胞。此外，这项提议有一个翻译目标，将为CD儿童开发新的治疗方法。我们以往的研究明确了CD患者大脑皮层正常和异常细胞的特征。这些研究发现，MRI的体积、神经元密度和电生理特性的变化类似于未成熟的发育中的皮质。基于这些发现，我们引入了发育不良假说，认为CD的组织病理学表现为正常的发育过程，如分子层和亚板细胞的凋亡和突触成熟减慢或停止，并伴随着灰质中间层晚出生锥体神经元数量的增加。我们认为，在发育迟缓的情况下，异位位置的CD细胞，如分子层和皮质下过渡区(STZ)，参与了癫痫的产生。此外，CD组织中的一些正常和异常细胞具有导致癫痫的不成熟突触特征。这些假说将通过：1)检测分子层和STZ神经元的形态和电生理特性；2)使用双重贴片记录检测正常和异常神经元之间的突触相互作用；3)检测影响GABAA受体和氯转运体、GABAB受体和mTOR通路(雷帕霉素)的药物组合对CD患者突触活动和诱发的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CD患者发病和癫痫发生的操作机制，以更好地确定癫痫发作的原因并开发治疗方法。 公共卫生相关性：在接受神经外科手术的儿童中，癫痫最常见的原因是大脑皮质畸形。我们认为，畸形的大脑不会充分发展和保留不成熟的特征。我们将通过临床、解剖学和电生理学方法检查手术中取出的脑组织来检验这一假设，以了解癫痫的原因并减轻儿童的癫痫发作。

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. PUBLIC HEALTH RELEVANCE: The most common cause of epilepsy in children undergoing neurosurgery is cortical malformations of the brain. We propose that malformed brains do not fully develop and retain immature features. We will test this hypothesis by using clinical, anatomical and electrophysiological approaches to examine brain tissue removed at surgery to understand the causes of epilepsy and alleviate seizures in children.