FOREBRAIN ORGANIZATION IN A NOVEL RAT

描述：(逐字摘自申请人的摘要)畸形 大脑皮层存在于超过1%的总人口中 以及至少20%-40%的顽固性癫痫患者。越来越多的证据 错位皮质神经元(皮质异位症)与 许多早发性癫痫和某些形式的精神发育迟滞。这个 缺乏合适的动物模型来研究先天性心脏病的自然发育 与癫痫相关的类人异位是一个主要障碍 理解：1)皮质异位在癫痫中的作用；2)癫痫 导致皮质异位的发育机制。 在对该项目的最初支持期间，我们确定并已 开始描述一种新的突变鼠(TITH)，它表现出与人类相似的特征 皮质异位症。有趣的是，一些TITY老鼠表现出自发的 在他们生命的相当一部分时间里持续的反复发作。 因此，TITY鼠代表了一种独特的动物，用于研究结构， 伴有条带的癫痫易发脑的功能和发育特点 异位症。本应用将集中于大脑皮层的干扰 TISH大鼠体内的抑制系统，目的是确定 在患有带状异位的大脑中诱发、触发和/或维持癫痫发作。 初步结果表明，结构中的基本扰动和 TISH大鼠体内存在GABA能系统的功能。这些修改是 处于使大脑皮质易于癫痫发作活动的位置。其他 初步研究结果表明，细胞增殖和细胞分化的错误 迁移在带状异位的发展中起着关键作用，而这些 这些事件可以选择性地干扰特定的中间神经元群体。这个 在这里提出的研究将扩大我们的努力，以了解机制 伴有带状异位的皮质中的癫痫和发育。 将解决以下具体目标：1)查明 条带异位症患者脑内GABA能中间神经元及其影响 海绵状反复惊厥对这些中间神经元的影响，2)阐明 导致带内中间神经元错位的发育事件 异位，通过比较错位的细胞增殖和 无序的神经元迁移，以及3)表征抑制功能。 已确定的位于异位与异位的投影神经元类别 在大脑皮质的正常位置，并定义自发的影响 反复发作对神经元功能特性的影响。建议数 研究将提供对结构、功能和 伴有条带异位的癫痫易发脑的发育。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Malformations of the cerebral cortex are present in over 1 percent of the general human population and at least 20 - 40 percent of intractable epileptics. Increasing evidence implicates misplaced cortical neurons (cortical heterotopia) in the etiology of many of the early-onset epilepsies and some forms of mental retardation. The lack of appropriate animal models for studying the natural development of human-like heterotopia associated with epilepsy represents a major impediment to understanding: 1) the roles of cortical heterotopia in epilepsy, and 2) the developmental mechanisms responsible for generating cortical heterotopia. During the initial period of support for this project, we identified and have begun to characterize a novel mutant rat (tish) that exhibits human-like cortical heterotopia. Interestingly, some tish rats display spontaneous recurrent seizures that persist over a considerable part of their life span. The tish rat thus represents a unique animal for investigating the structural, functional, and developmental aspects of a seizure prone brain with band heterotopia. The present application will focus on disturbances in cortical inhibitory systems in the tish rat with the goal of identifying mechanisms that predispose, trigger and/or maintain seizures in a brain with band heterotopia. Preliminary results indicate that fundamental disturbances in the structure and function of GABAergic systems are present in tish rats. These modifications are in a position to predispose the tish cortex to seizure activity. Other preliminary findings indicate that errors in cellular proliferation and migration play key roles in the development of band heterotopia, and these events could selectively disturb specific populations of interneurons. The studies proposed here will expand our effors to understand mechanisms of epilepsy and developmnet in a cortex with band heterotopia. The following specific aims will be addressed: 1) Identify disturbances in GABAergic interneurons in a brain with band heterotopia and define the effects of spontaineous recurrent seizures on these interneurons, 2) Elucidate developmental events contributing to the misplacement of interneurons in band heterotopia, by comparing the roles of misplaced cellular proliferation and disordered neuronal migration, and 3) Characterize inhibitory function in identified classes of projection neruons located at heterotopic versus normotopic positions in the tish cortex, and define the effects of spontaneous recurrent seizures on the functionnal properties of neurons. The proposed studies will provide fundamental insights into the structure, function and development of a seizure-prone brain with band heterotopia.