Posttraumatic epilepsy induced by fluid percussion injury in the rat

这项建议的总体目标是开始调查导致疾病发生的机制。 液压冲击伤(FPI)所致创伤后癫痫(PTE)的研究进展 在我们最新的工作中，我们发现并描述了 不同类型的慢性自发性复发性部分性发作(CSRPSs 1、2和3级) 2)发现rpFPI诱导的PTE是一种进行性疾病 这导致在受伤几个月后，出现内侧-颞叶癫痫(MTLE)，并伴有双重病理。现在 提案将集中于定义rpFPI诱导的CSRPS的神经底物，关于 FPI诱导CSRPS的异质性及其发生发展机制。 具体目的：检验以下假设：1)rpFPI部位的额顶新皮质 发展成早期癫痫灶，导致1级和2级癫痫发作，而海马体和 梨状皮质形成癫痫灶，随后导致3级癫痫发作。2)这种概率 发生肺间质纤维化后的PTE，以及发作类型、频率和持续时间，其潜在的 病理学及其时间进展取决于损伤的程度和位置。3) 创伤后早期癫痫灶内的神经元和突触活动是必需的 癫痫的发生。4)早期癫痫灶介导的点燃样细胞现象是 负责海马区癫痫的发生。5)异丙肾上腺素的药理效应 随着疾病的发展，癫痫会随着时间的推移而变化，这是癫痫发作类型和颞叶的一种功能。 硬化症。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PTE危险因素和基本机制研究中的应用。 因为这种啮齿动物模型在表型和病因学上存在着无与伦比的相似性 人类PTE收集的数据将有助于阐明更相关的起源和 PTE的进展，以及模型的更好标准化，以利于基本和 翻译研究的努力。

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 ofPTE. 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.