Posttraumatic epilepsy induced by fluid percussion injury in the rat

描述（由申请人提供）：本提案的总体目标是开始研究大鼠脑震荡闭合性头部损伤的相关模型——液体撞击损伤（FPI）诱发的创伤后癫痫（PTE）的发生和发展机制。在我们最近的工作中，我们1)发现并描述了大鼠吻侧副趾FPI （rpFPI）后不同类型的慢性自发性复发性部分性癫痫发作（CSRPSs等级1、2和3）；2)发现rpfpi诱导的PTE是一种进行性疾病，在损伤后数月导致具有双重病理的中颞叶癫痫（MTLE）。本文将重点阐述rpfpi诱导的CSRPSs的神经底物，fpfpi诱导的CSRPSs异质性的机制，以及它们的发生和发展机制。具体目的：验证以下假设：1)rpFPI部位的额顶叶新皮层发育为早期癫痫灶，负责1级和2级癫痫发作，而海马和梨状皮质发育为晚期癫痫灶，负责3级癫痫发作。2) FPI后发生PTE的概率、发作类型、频率和持续时间、潜在病理及其时间进展取决于损伤的程度和部位。3)早期癫痫病灶内的神经元和突触活动是创伤后癫痫发生的必要条件。4)一种由早期癫痫灶介导的点火样细胞现象是海马癫痫发生的原因。5) fpi诱发癫痫的药物反应性随时间、疾病进展、癫痫发作类型和颞叶硬化的变化而变化。此外，我们的目标是建立一个fpi诱导的PTE小鼠模型，引入基因工程小鼠在PTE危险因素和基本机制的研究中，由于该啮齿动物模型与人类PTE之间存在无与伦比的表型和病因相似性，收集的数据将有助于阐明PTE发生和发展的更多相关机制。为了更好地标准化模型，为了基础研究和转化研究的努力。

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.