Abstracts

Rationale: Traumatic brain injury (TBI) is a leading cause of posttraumatic epileptogenesis, although the mechanisms underlying this relationship remain unclear. Sprouting of mossy fibers into the inner molecular layer is hypothesized to support recurrent excitation in the dentate gyrus in animal models examining the cellular basis of chronic epilepsy. Human epidemiology suggests that the development of posttraumatic epilepsy is related to injury severity. This study tests the hypothesis that injury severity is related to mossy fiber sprouting in the dentate gyrus and development of recurrent spontaneous seizures in a mouse model of posttraumatic epilepsy. Methods: Unilateral controlled cortical impact injury (1.0 mm impact depth) was administered to young-adult CD1 mice. Mice were monitored for behavioral seizures 6-10 weeks post-injury. Timm and Nissl staining was performed on brain sections to examine the extent of damage to cortical structure and mossy fiber organization. Results: Limited mossy fiber sprouting into the inner molecular layer of the dentate gyrus was associated with structural damage that was restricted to the neocortex near the injury epicenter. However, damage that extended into underlying hippocampal structures was associated with more robust mossy fiber sprouting near the injury site. Furthermore, animals that received damage extending into the hippocampus developed spontaneous behavioral seizures 6-10 weeks following the injury; spontaneous seizures were not observed in mice with damage limited to the neocortex. Studies are ongoing to determine if mouse strain (e.g., C57Bl/6 or CD1) is related to development of posttraumatic epilepsy in this model after comparable injury. Conclusions: This study elucidates the extent of structural damage associated with indicators of epileptogenesis, including mossy fiber sprouting and spontaneous seizure generation. Severe damage, especially which included hippocampal lesion, was more likely to be associated with observations of spontaneous seizures and mossy fiber sprouting. The extent of cortical damage after cortical contusion may predict the development of posttraumatic epilepsy in this model.