FOREBRAIN ORGANIZATION IN A NOVEL RAT

新型大鼠的前脑组织

• 批准号: 6393713
• 负责人: KEVIN Scott LEE
• 金额: $ 29.6万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-12-18 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393713
• 关键词: GABA receptor; brain disorders; developmental neurobiology; epilepsy; interneurons; laboratory rat; neural inhibition; neuroanatomy; neurogenesis; prosencephalon; synapses

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.

描述：（逐字摘自申请人摘要）畸形 大脑皮层存在于总人口的 1% 以上 以及至少 20% - 40% 的顽固性癫痫患者。越来越多的证据 暗示错位的皮质神经元（皮质异位）与病因学有关 许多早发性癫痫和某些形式的智力低下。这 缺乏合适的动物模型来研究自然发育 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） 负责产生皮质异位的发育机制。 在支持该项目的初期，我们确定并已 开始表征一种表现出类似人类的新型突变大鼠（tish） 皮质异位。有趣的是，一些tish大鼠表现出自发的 反复发作的癫痫发作在其一生的相当长的一段时间内持续存在。 因此，蒂什鼠代表了一种独特的动物，可用于研究结构、 癫痫易发性大脑的功能和发育方面 异位。本申请将重点关注皮质的干扰 tish 大鼠的抑制系统，目的是确定以下机制： 诱发、触发和/或维持带状异位大脑的癫痫发作。 初步结果表明，结构和结构中的基本扰动 Tish 大鼠体内存在 GABA 能系统的功能。这些修改是 处于使蒂什皮层易于癫痫发作的位置。其他 初步研究结果表明细胞增殖和 迁移在能带异位的发展中起着关键作用，这些 事件可能会选择性地干扰特定的中间神经元群体。这 这里提出的研究将扩大我们对理解机制的努力 癫痫和带状异位皮质的发育。 将解决以下具体目标： 1) 识别干扰 带状异位大脑中的 GABA 能中间神经元并定义其影响 这些中间神经元自发性复发性癫痫发作的影响，2）阐明 导致带内中间神经元错位的发育事件 异位，通过比较错位细胞增殖和 神经元迁移紊乱，以及 3) 表征抑制功能 确定了位于异位与异位的投射神经元类别 蒂什皮质中的正常位置，并定义自发的影响 反复发作对神经元功能特性的影响。拟议的 研究将为结构、功能和 具有带状异位的易癫痫发作的大脑的发育。