Penetrating brain injury and copper fragments in a rat model of posttraumatic Epilepsy

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Project Summary Traumatic brain injury (TBI) is a major neurological problem for both civilians and military personnel, and one of the most devastating outcomes is posttraumatic epilepsy (PTE). Several types of animal models have been developed to attempt to replicate the major features of TBI and PTE. Many research groups have attempted to use these animal models in rodents to study PTE, but we and several other groups have found that only a small fraction of brain-injured rodents actually develop genuine spontaneous recurrent seizures, which are the hallmark of PTE. Actually, many clinical reports of retrospective studies of PTE, including the classical work of Annegers and coworkers (1998), have found only a small fraction of the many patients who have experienced TBI actually develop PTE; however, for those individuals it can be profoundly debilitating. The experiments in this research proposal aim to modify one of these animal models, controlled cortical impact (CCI), in a manner to make it include a simulation of a penetrating TBI with small metal fragments, as would occur with a gunshot wound or a missile injury from an explosion. Our preliminary studies strongly suggest that combining a CCI- injury with copper fragments converts it from one with a relatively small number of seizures to one where most animals have spontaneous recurrent seizures and they occur at a relatively high frequency. Our proposed experiments aim to test the hypothesis that a TBI with copper fragments, as would occur in a modern gunshot wound to the head, greatly enhances the spontaneous recurrent seizures in the CCI model of TBI. These studies would not only provide critical new insights into what characteristics of the TBI actually underlie some devastating forms of PTE, but would also provide the framework for future modifications of animal models of TBI to allow us to provide better symptomatic treatment of the spontaneous seizures, and to find better therapies to block the development of posttraumatic epileptogenesis.