Pathophysiology of Developing Dysplastic Human Cortex

神经外科手术是儿童难治性癫痫的常用治疗方法。大约一半 的手术病例有皮质发育不良(CD)，包括皮质分层障碍、异位神经元和 畸形的巨细胞神经元和气球细胞。其他的有非CD的病理，如脑梗塞 和拉斯穆森综合征。本研究项目的目标是检查电生理学和 儿童CD组织中细胞的解剖学特性以辨别导致癫痫发生的机制。在……里面 在之前的资助阶段，我们发现巨细胞神经元显示电压门控钙离子增加。 电流，巨细胞神经元和约30%的锥体神经元对镁离子的敏感性降低 NMDA受体类似于未成熟皮质。气球细胞不显示活性膜特性或 突触活动。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GABA，更大的层1诱发 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由一定比例的细胞组成 保留未成熟的GABA信号特性，与正常的成熟样锥体细胞相互作用，产生 “癫痫前期”条件和癫痫发作。这一更新将通过在严重的情况下确定 CD IF：1)突触信号类似于以GABA(而不是谷氨酸)为主的未成熟皮层 神经递质；2)巨细胞和一些锥体神经元上的GABAA受体呈未成熟状态 特性，如去极化反转电位；3)从GABA增强GABA功能 改变药物是兴奋性的和“致痫的”；4)中间神经元表现出不成熟的特征。 与锥体神经元自发的节律性“起搏器”GABA活动有关。结果是 这些实验将揭示与Cd相关的癫痫发生的发育病理机制。 这是无法从动物CD模型中获得的，并开始翻译研究，将提供 儿童CD合并癫痫合理药物治疗的探讨。

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.