Posttraumatic epilepsy induced by fluid percussion injury in the rat

描述(由申请人提供)：这项建议的总体目标是开始调查液压冲击伤(FPI)引起的创伤后癫痫(PTE)的发生和发展机制，这是一种相关的大鼠脑震荡闭合性头部损伤模型。在我们最新的工作中，我们1)发现并表征了不同类型的慢性自发性复发性部分性癫痫(CSRPSs分级为1、2和3级)；2)发现rpFPI诱导的PTE是一种进行性疾病，在损伤后几个月导致具有双重病理的内侧-颞叶癫痫(MTLE)。目前的建议将集中在定义rpFPI诱导的CSRPS的神经底物，FPI诱导的CSRPS的异质性机制，以及它们的发生和发展机制。具体目的：验证以下假设：1)rpFPI部位的额顶新皮质发育成早期癫痫灶，导致1级和2级癫痫发作，而海马区和梨状皮质在后期形成癫痫灶，引起3级癫痫发作。2)肺损伤后发生PTE的概率、发作类型、发作频率和发作持续时间、其基本病理和时间进展取决于损伤的程度和位置。3)早期癫痫灶内的神经元和突触活动是发生创伤后癫痫所必需的。4)早期癫痫灶介导的点燃样细胞现象参与了海马区癫痫的发生。5)作为癫痫发作类型和颞叶硬化症的函数，FPI诱导癫痫的药理反应性随着疾病的进展而变化。此外，我们的目标是建立一种FPI诱导的PTE的小鼠模型，以介绍基因工程小鼠在研究PTE的危险因素和基本机制方面的应用。由于这种啮齿动物模型在表型和病因学上与人类PTE存在着无与伦比的相似性，所收集的数据将有助于阐明PTE发生和发展的更相关机制，并使该模型更好地标准化，从而有利于基础研究和翻译研究。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to begin the investigation of the mechanisms responsible for the genesis and progression of posttraumatic epilepsy (PTE) induced by fluid percussion injury (FPI), a relevant model of concussive closed head injury in the rat. In our most recent work we 1) discovered and characterized different types of chronic spontaneous recurrent partial seizures (CSRPSs grade 1, 2 and 3) following rostral parasaggital FPI (rpFPI) in the rat; 2) discovered that rpFPI-induced PTE is a progressive disorder that results, months after injury, in mesial-temporal lobe epilepsy (MTLE) with dual pathology. The present proposal will focus on defining the neural substrates of rpFPI-induced CSRPSs, on the mechanisms of heterogeneity of FPI-induced CSRPSs, and on their mechanisms of genesis and progression. Specific Aims: to test the following hypotheses: 1) that the frontal-parietal neocortex at the site of rpFPI develops into the early epileptic focus, responsible for grade 1 and 2 seizures, while hippocampus and piriform cortex develop epileptic foci, responsible for grade 3 seizures, at later times. 2) that the probability of developing PTE following FPI, as well as seizure type, frequency and duration, their underlying pathology, and their temporal progression, depends on the degree and location of the injury. 3) that neuronal and synaptic activity within the incipient early epileptic focus is required for posttraumatic epileptogenesis to occur. 4) that a kindling-like cellular phenomenon mediated by the early epileptic focus is responsible for hippocampal epileptogenesis. 5) that the pharmacological responsiveness of FPI-induced epilepsy changes with time, as the disease progresses, as a function of seizure type and temporal lobe sclerosis. In addition, we aim to develop a murine model of FPI-induced PTE to introduce the use of genetically engineered mice in the investigation of risk factors and basic mechanisms of PTE. Because of the unparalleled phenotypic and etiological similarities existing between this rodent model and human PTE the data collected will lead to the elucidation of more relevant mechanisms of genesis and progression of PTE, and to a better standardization of the model to the advantage of both basic and translational research efforts.