Pathophysiology of Developing Dysplastic Human Cortex

描述(申请人提供)：神经外科手术是儿童难治性癫痫的常用治疗方法。约一半的手术病例有皮质发育不良(CD)，包括皮质分层障碍、异位神经元、变形的巨细胞神经元和气球细胞。其他人有非CD病理，如脑梗塞和拉斯穆森综合征。本研究项目的目的是检测儿童CD组织中细胞的电生理学和解剖学特性，以识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性钙电流增加，巨细胞神经元和大约30%的锥体神经元表现出类似于未成熟皮质的镁离子敏感的NMDA受体减少。气球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终末更多的GABA，更大的第一层诱发的GABA介导的电流，具有去极化反转电位的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由保留不成熟的GABA信号特性的细胞的一部分组成，这些细胞与正常的成熟的类锥体细胞相互作用，产生“癫痫前”条件和癫痫发作。这一更新将通过确定严重CD是否：1)突触信号类似于以GABA(而不是谷氨酸)为主要神经递质的未成熟皮质；2)巨细胞和一些锥体神经元上的GABAA受体显示出不成熟的特征，如去极化的逆转电位；3)通过改变GABA的药物增强GABA的功能是兴奋性的和“促癫痫”的；以及4)神经元间表现出与锥体神经元上自发的节律性“起搏器”GABA活动有关的未成熟特征。这些实验的结果将揭示从动物CD模型中无法获得的与CD相关的癫痫发生的发育病理机制，并开始转译研究，为儿童CD合并癫痫的合理药物治疗提供洞察力。

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.