Pathophysiology of Developing Dysplastic Human Cortex

人类皮质发育不良的病理生理学

• 批准号: 7049843
• 负责人: GARY W. MATHERN
• 金额: $ 31.29万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049843
• 关键词: AMPA receptors; GABA receptor; NMDA receptors; biocytin; brain electrical activity; child (0-11); clinical research; congenital brain disorder; developmental neurobiology; disease /disorder etiology; electrocorticography; electrophysiology; epilepsy; glutamate receptor; human subject; immunocytochemistry; in situ hybridization; kainate; neocortex; neuroanatomy; neuropathology; receptor expression

DESCRIPTION (provided by applicant): Resective neurosurgery is a frequent treatment for children with therapy-resistant epilepsy. About half of surgical cases have cortical dysplasia (CD), consisting of cortical dyslamination, heterotopic neurons, and dysmorphic cytomegalic neurons and balloon cells. The others have non-CD pathologies such as infarcts and Rasmussen syndrome. The goals of this research project are to examine the electrophysiologic and anatomic properties of cells in pediatric CD tissue to discern mechanisms that lead to epileptogenesis. In the previous funding period, we found that cytomegalic neurons displayed increased voltage-gated calcium currents, and cytomegalic neurons and about 30% of pyramidal neurons showed decreased Mg++ sensitive NMDA receptors similar to immature cortex. Balloon cells did not display active membrane properties or synaptic activity. In Preliminary studies, we also found that severe CD has other immature features. These include more GABA than glutamate spontaneous synaptic currents and terminals, greater layer 1 evoked GABA-mediated currents, GABA-A receptors with depolarized reversal potentials, longer GABA-A receptor decay time constants, and more interneurons than expected including recently discovered cytomegalic GABA neurons. These findings lead us to hypothesize that severe CD consists of a proportion of cells that retain immature GABA signaling properties interacting with normal mature-like pyramidal cells to produce "pro-epileptic" conditions and seizures. This renewal will address this hypothesis by determining in severe CD if: 1) Synaptic signaling is similar to immature cortex with GABA (not glutamate) as the predominant neurotransmitter; 2) GABAA receptors on cytomegalic and some pyramidal neurons show immature characteristics, such as depolarized reversal potentials; 3) Enhancement of GABA function from GABA altering medications are excitatory and "pro-epileptic"; and 4) Interneurons display immature characteristics associated with spontaneous rhythmic "pacemaker" GABA activity on pyramidal neurons. The results of these experiments will discern developmental pathologic mechanisms of epileptogenesis associated with CD that cannot be obtained from animal CD models, and begin translational research studies that will provide insight into rational pharmacological treatments for pediatric CD patients with epilepsy.

描述（由申请人提供）：改善神经外科是对耐治疗癫痫患者的常见治疗方法。大约一半的手术病例患有皮质发育不良（CD），由皮质障碍，异位神经元以及畸形巨细胞神经元和气球细胞组成。其他的具有非CD病理，例如梗塞和拉斯穆森综合征。该研究项目的目标是检查小儿CD组织中细胞的电生理和解剖学特性，以识别导致癫痫发生的机制。在上一个资金期间，我们发现巨型神经元显示出增加的电压门控钙电流，巨细胞神经元和约30％的锥体神经元显示出MG ++敏感的NMDA受体的降低，类似于不成熟的皮质。球囊细胞没有显示活跃的膜特性或突触活动。在初步研究中，我们还发现严重的CD具有其他不成熟的特征。这些包括比谷氨酸自发突触电流和末端，更大的第1层诱发的GABA介导的电流，具有去极化反转电势的GABA-A受体，更长的GABA-A受体衰减时间常数，以及包括最近发现的细胞瘤GABAILIC GABA神经元在内的gaba-A受体。这些发现导致我们假设严重的CD由一定比例的细胞组成，这些细胞保留了与正常成熟的成熟金字塔细胞相互作用的未成熟GABA信号传导特性，以产生“促发作性”条件和癫痫发作。此更新将通过在严重的CD中确定以下情况来解决这一假设：1）突触信号传导类似于与GABA（非谷氨酸）作为主要神经递质的未成熟皮质； 2）在巨型和某些锥体神经元上的GABAA受体显示出未成熟的特征，例如去极化的逆转电位； 3）通过改变GABA的药物增强GABA功能是兴奋性的，并且“癫痫性”； 4）中间神经元显示出与自发性节奏的“起搏器” GABA在金字塔神经元上的无效特征。这些实验的结果将辨别与CD相关的癫痫发生的发育病理学机制，这些机制无法从动物CD模型中获得，并开始转化研究研究，这些研究将为患有癫痫患者的儿科CD患者提供洞察力。