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）：癫痫是一种频繁的神经系统疾病，大约25％的儿童患有药物难治性癫痫发作。在接受神经外科手术的药疗癫痫患者中，皮质发育不良（CD）是最常见的病因。该提案的重点是识别儿科癫痫手术患者CD的癫痫发生机制。人类手术组织的使用很重要，因为CD的动物模型并未完全复制人类中的组织病理学，尤其是异常的巨细胞神经元和球囊细胞。此外，该提案具有转化目的，将为CD儿童开发新的治疗方法。我们以前的研究确定了CD患者脑皮质中正常细胞和异常细胞的特征。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。基于这些发现，我们引入了脑发育障碍假说，该假说提出CD的组织病理学代表了正常发育过程的组织，例如分子层和子板中细胞的细胞凋亡以及突触成熟度和突触成熟的速度缓慢或停止，或与后期的Pyramidal神经元相关的较高的灰色含量分层的较高的灰色质量分层。我们建议，随着发育延迟的延迟，异位位置的CD细胞（例如分子层和皮层下过渡区（STZ））参与了癫痫发作。另外，CD组织中的某些正常和异常细胞具有促尿液的未成熟突触特征。这些假设将通过：1）检查分子层和STZ中神经元的形态和电生理特性； 2）使用双斑记录检查正常神经元和异常神经元之间的突触相互作用； 3）检查影响GABAA受体和氯化物转运蛋白，GABAB受体以及MTOR途径（Rapamycin）对突触活性的急性作用，并在CD病例中诱导的癫痫表现。这些研究之所以重要，是因为它们阐明了CD患者的发病机理和癫痫发生的操作机制，以更好地定义癫痫发作的原因并开发治疗。