Pathophysiology of Developing Dysplastic Human Cortex

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用治疗方法。大约一半的手术病例有皮质发育不良（CD），包括皮质层积异常、异位神经元、畸形的巨细胞神经元和球囊细胞。其他人则有非乳糜泻病理，如梗死和拉斯穆森综合征。本研究项目的目的是检查儿童乳糜泻组织中细胞的电生理和解剖特性，以辨别导致癫痫发生的机制。在之前的资助期内，我们发现巨细胞神经元显示出电压门控钙电流的增加，巨细胞神经元和大约30%的锥体神经元显示出与未成熟皮层相似的Mg++敏感NMDA受体的减少。球囊细胞没有表现出活跃的膜特性或突触活性。在初步研究中，我们还发现严重的乳糜泻还有其他不成熟的特征。其中包括比谷氨酸更多的GABA自发突触电流和终末，更大的第1层诱发的GABA介导电流，具有去极化逆转电位的GABA- a受体，更长的GABA- a受体衰变时间常数，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。这些发现使我们假设严重的CD由一部分保留未成熟GABA信号特性的细胞组成，这些细胞与正常的成熟锥体细胞相互作用，产生“癫痫前”状态和癫痫发作。这一更新将通过确定严重CD患者是否：1)突触信号与未成熟皮层相似，以GABA（而非谷氨酸）为主要神经递质；2) GABAA受体在巨细胞和部分锥体神经元上表现出去极化逆转电位等不成熟特征；3) GABA改变药物对GABA功能的增强具有兴奋性和“促癫痫性”；4)中间神经元表现出与锥体神经元自发节律性“起搏器”GABA活性相关的不成熟特征。这些实验的结果将揭示与乳糜泻相关的癫痫发生的发育病理机制，这是无法从动物乳糜泻模型中获得的，并将开始转化研究，为儿科乳糜泻合并癫痫患者的合理药物治疗提供见解。

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.