Abstracts

Rationale: Trauma is often accompanied by the delayed development of temporal lobe epilepsy, but the underlying mechanisms by which head injury leads to chronic seizures remain poorly understood. Identification of experimental injury models that display similar pathology to injury-induced epilepsy in humans should help to elucidate the means by which the injured brain becomes epileptic. The present study tested the hypothesis that mice develop spontaneous seizures and undergo synaptic reorganization in the dentate gyrus after controlled cortical impact injury. Methods: Adult male CD1 mice were administered mild (0.5mm injury depth) or severe (1.0mm injury depth) controlled cortical impact injury. Mice were monitored for spontaneous seizure activity beginning 42 days after injury until the day of experimentation. Contralateral and ipsilateral dentate gyri were examined anatomically for the presence of mossy fiber sprouting 7 days or 42-71 days post-injury. In addition, extracellular field-potential recordings were made to assess network excitability within the dentate gyrus 42-71 days after brain injury. Results: Spontaneous seizures developed in 20% of mice after mild and 36% of mice after severe injury. Timm’s staining revealed mossy fiber sprouting in the dentate gyrus localized in septal slices ipsilateral to the injury after mild (20% of mice) and severe (55% of mice), but not in control mice. Stimulation of perforant path revealed a significant reduction (P < 0.01) in paired-pulse responses in dentate granule cells at 20ms (47%) and 40ms (59%) interpulse intervals in slices from injured animals with mossy fiber sprouting compared to controls; no difference was detected at 80ms or 160ms intervals. Responses in slices from injured animals that did not display mossy fiber sprouting were not different from controls at any interval. In the presence of Mg2+- free ACSF containing 100µM picrotoxin, slices with mossy fiber sprouting were characterized by spontaneous and hilar-evoked epileptiform activity in the dentate gyrus. These alterations were more commonly observed after severe versus mild injury. Conclusions: These findings indicate that spontaneous posttraumatic seizures as well as structural and functional network changes often associated with temporal lobe epilepsy develop in the mouse dentate gyrus by 71d after controlled cortical impact injury. This model may be valuable in identifying mechanisms of epileptogenesis subsequent to traumatic brain injury.