Developing a rat model of posttraumatic epilepsy

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The goal of the current application is to develop a rodent model of post-traumatic epilepsy. The importance of such a model arises from two related but separate observations: 1) Post-traumatic epilepsy is of considerable clinical concern. The population of individuals with traumatic head injury has a significantly higher risk of developing epilepsy than the uninjured population. 2) Post-traumatic epilepsy is often associated with a variable "latent" period between injury and appearance of a clinical seizure disorder. This latent period provides an important window into potential epileptogenic processes that can be targeted with new anti-epileptogenic therapies. While there is a large body of research focusing on traumatic brain injury (TBI), there has been surprisingly little experimental/animal model work on post-traumatic epilepsy. This gap is likely due, at least in part, to the difficulty in demonstrating a chronic epileptic condition in rodents (rats or mice) following experimental manipulations that produce traumatic brain injury (e.g., fluid percussion, weight drop, controlled cortical impact). Investigators have produced chronic seizure states in rats following status epilepticus, but at best have produced a more seizure-prone animal (lower seizure threshold) following TBI. We propose to develop a rat model of TBI in which a latent period is followed by a chronic seizure state. We will approach this goal initially by manipulating key variables of controlled cortical impact (CCI) (e.g., position of impact, degree of penetration), Based on the neuropathology mostoften associated with status epilepticus models, we hypothesize that TBI insults that result in s!gnificant damage to ventral hippocampus, and/or in bilateral hippocampal injury and reorganization, will result in chronic seizure activity - especially if the injury is associated with significant post-trauma hypoxia. Once a reliable model has been developed, we will begin to assess the contributions of predisposing factors (e.g., genetics, early insult) to the establishment of a post-traumatic epileptic condition. Determination of seizure activity in animals with TBI will be carried': out using long-term video/EEG telemetric monitoring. In addition, animals will be tested for seizure threshold (latency to flurothyl-induced seizures). Treated and tested animals will be sacrificed for histological analysis of damage.