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液压冲击损伤（FPI）诱导的创伤后癫痫（PTE）的发生和进展机制，FPI是大鼠脑震荡闭合性损伤的相关模型。在我们最近的工作中，我们1）发现并表征了大鼠在头侧附沟旁FPI（rpFPI）后不同类型的慢性自发复发性部分性癫痫发作（CSRPS 1级、2级和3级）; 2）发现rpFPI诱导的PTE是一种进行性疾病，在损伤后数月，导致具有双重病理学的内侧颞叶癫痫（MTLE）。本建议将集中在定义的神经基板的rpFPI诱导的CSRPSs，在FPI诱导的CSRPSs的异质性的机制，并在其发生和发展的机制。具体目标：为了检验以下假设：1）rpFPI位点处的额顶叶新皮层发展成早期癫痫病灶，负责1级和2级癫痫发作，而海马和梨状皮质发展癫痫病灶，负责3级癫痫发作，在稍后的时间。2)FPI后发生PTE的可能性，以及癫痫发作类型、频率和持续时间，其潜在病理学及其时间进展，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所必需的。4)由早期癫痫灶介导的点燃样细胞现象是海马癫痫发生的原因。5)FPI诱导的癫痫的药理学反应性随着时间的推移而变化，随着疾病的进展，作为癫痫发作类型和颞叶硬化的函数。此外，我们的目标是建立一个小鼠模型的FPI诱导的PTE介绍使用基因工程小鼠在调查的危险因素和PTE的基本机制。由于这种啮齿动物模型和人类PTE之间存在着无与伦比的表型和病因学相似性，因此收集的数据将有助于阐明PTE发生和进展的更多相关机制，并使模型更好地标准化，以利于基础和转化研究工作。

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.