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）：切除性神经外科手术是治疗难治性癫痫儿童的常见治疗方法。大约一半的手术病例患有皮质发育不良（CD），包括皮质层层叠不良、异位神经元、畸形巨细胞神经元和气球细胞。其他人患有非 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儿科 CD 组织中细胞的电生理学和解剖学特性，以辨别导致癫痫发生的机制。在之前的资助期间，我们发现巨细胞神经元表现出电压门控钙电流增加，并且巨细胞神经元和约30%的锥体神经元表现出类似于未成熟皮质的Mg++敏感NMDA受体减少。球囊细胞不表现出活跃的膜特性或突触活性。在初步研究中，我们还发现重度CD还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多的 GABA、更大的第 1 层诱发的 GABA 介导电流、具有去极化反转电位的 GABA-A 受体、更长的 GABA-A 受体衰减时间常数以及比预期更多的中间神经元，包括最近发现的巨细胞 GABA 神经元。这些发现使我们推测，严重 CD 由保留未成熟 GABA 信号传导特性的一部分细胞组成，这些细胞与正常成熟样锥体细胞相互作用，产生“促癫痫”病症和癫痫发作。这项更新将通过确定严重 CD 中是否满足以下条件来解决这一假设： 1) 突触信号传导类似于未成熟的皮质，以 GABA（不是谷氨酸）作为主要神经递质； 2）巨细胞和部分锥体神经元上的GABAA受体表现出不成熟的特征，如去极化反转电位； 3) 改变 GABA 的药物增强 GABA 功能，具有兴奋性和“促癫痫”作用； 4) 中间神经元表现出与锥体神经元自发节律“起搏器”GABA 活性相关的不成熟特征。这些实验的结果将辨别与 CD 相关的癫痫发生的发育病理机制，而这些机制无法从动物 CD 模型中获得，并开始转化研究，为儿童 CD 癫痫患者的合理药物治疗提供见解。