FOREBRAIN ORGANIZATION IN A NOVEL RAT

描述：（申请人摘要中的逐字记录） 大脑皮层存在于超过1%的普通人群中， 和至少20 - 40%的难治性癫痫患者。越来越多的证据 暗示错位的皮质神经元（皮质异位症）的病因， 许多早发性癫痫和某些形式的智力迟钝。的 缺乏适当的动物模型来研究自然发展， 与癫痫相关的类人异位是一个主要障碍， 了解：1）皮质异位在癫痫中的作用，2） 负责产生皮质异位的发育机制。 在支持该项目的初期，我们确定并 开始描述一种新的突变大鼠（tish）， 皮质异位有趣的是，一些tish老鼠表现出自发的 反复发作，持续了相当长的一段时间的生命。 因此，tish大鼠代表了一种独特的动物， 功能和发育方面的癫痫倾向的大脑与乐队 异位症本申请将集中于皮层神经元的干扰。 抑制系统，目的是鉴定 易患、触发和/或维持带状异位脑中的癫痫发作。 初步结果表明，结构中的基本扰动和 GABA能系统的功能存在于tish大鼠中。这些修饰 使tish皮层易于癫痫发作其他 初步研究结果表明，细胞增殖和 迁移在带状异位症的发展中起着关键作用， 事件可以选择性地干扰特定的中间神经元群体。的 这里提出的研究将扩大我们的努力，以了解机制， 癫痫和带状异位皮质发育。 将处理以下具体目标：1）确定 带状异位脑内GABA能中间神经元及其影响 这些中间神经元上自发性复发性癫痫发作，2）阐明 导致带状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 神经元迁移障碍，以及3）表征神经元迁移的抑制功能 确定的投射神经元类别位于异位与 在tish皮层的正常位置，并定义自发的影响， 反复发作对神经元功能特性的影响。拟议 研究将提供基本的见解，结构，功能和 发展成带状异位的脑畸形倾向。

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.