Pathophysiology of Developing Dysplastic Human Cortex

人类皮质发育不良的病理生理学

基本信息

批准号：
8374107
负责人：
Carlos T Cepeda
金额：
$ 31.86万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374107
关键词：
Abnormal Cell Acute Affect Agonist Animal Model Apoptosis Barbiturates Brain Bumetanide Butyric Acids Cells Cellular Morphology Cerebral cortex Cerebrum Characteristics Child Childhood Chloride Ion Chlorides Clinical Cognitive Cortical Dysplasia Cortical Malformation Development Developmental Process Drug Combinations Electrophysiology (science)Epilepsy Epileptogenesis Etiology Frequencies Functional disorder Generations Glutamates Goals Histopathology Human Infant Interneurons Knowledge Link Location Magnetic Resonance Imaging Membrane N-Methylaspartate Neuroglia Neurologic Neurons Normal Cell Operative Surgical Procedures Pathogenesis Pathway interactions Patients Property Public Health Radial Refractory Regimen Seizures Sirolimus Structure of molecular layer of cerebellar cortex Synapses Synaptic Membranes Testing Tissues barbituric acid salt base brain tissue density disability gamma-Aminobutyric Acid gray matter hippocampal pyramidal neuron human FRAP1 protein neurosurgery public health relevance receptor research study social synaptogenesis

项目摘要

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.

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% 的儿童患有医学难治性癫痫发作。在接受神经外科手术的耐药性癫痫儿童中，皮质发育不良（CD）是最常见的病因。该提案的重点是确定患有 CD 的小儿癫痫手术患者的癫痫发生机制。使用人类手术组织很重要，因为 CD 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，该提案还有一个转化目标，即为患有 CD 的儿童开发新的治疗方法。我们之前的研究确定了 CD 患者大脑皮层正常和异常细胞的特征。这些研究发现 MRI 体积、神经元密度和电生理特性的变化类似于未成熟的皮质发育。基于这些发现，我们提出了成熟性大脑发育假说，该假说提出 CD 的组织病理学代表正常发育过程（例如分子层和亚板细胞凋亡以及突触成熟）随着数量增加而减慢或停止的组织。灰质中间层的晚生锥体神经元。我们认为，随着发育延迟，分子层和皮质下过渡区 (STZ) 等异位位置的 CD 细胞参与癫痫发作的发生。此外，CD组织中的一些正常和异常细胞具有促癫痫的不成熟突触特征。这些假设将通过以下方式进行检验：1）检查分子层和 STZ 中神经元的形态和电生理特性； 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) 检查影响 GABAA 受体和氯离子转运蛋白、GABAB 受体和 mTOR 通路（雷帕霉素）的药物组合对 CD 病例突触活动和诱发癫痫样放电的急性影响。这些研究意义重大，因为它们阐明了 CD 患者发病机制和癫痫发生的运作机制，以便更好地确定癫痫发作的原因并开发治疗方法。