Abstracts

Rationale: Epilepsy is a common, debilitating disease for which there is no effective preventative. Developing novel therapies will require further understanding of the disease pathology. Here, we assessed the relationship between abnormal, newly-generated, dentate granule cells (DGCs) and epileptogenesis. DGCs have long been implicated in temporal lobe epilepsy (TLE), as they regulate excitatory signaling through the hippocampus and exhibit neuroplastic changes during epileptogenesis. Furthermore, DGCs are unusual in that they are continually generated into adulthood, with aberrant integration of newly-generated DGCs underlying the majority of restructuring in the dentate gyrus during disease progression. While it is known that these abnormal networks promote abnormal neuronal firing and hyperexcitability, it has yet to be established whether they directly contribute to seizure generation. Here, we sought to determine whether a positive correlation existed between the number of abnormal, newly-generated granule cells in an animal, and the frequency of spontaneous seizures. Methods: In this study, we utilized mouse cre-loxP technology to selectively activate GFP in postnatally-generated hippocampal granule cells during the development of epilepsy. Mice were rendered epileptic by inducing status epilepticus with pilocarpine. Two months after status epilepticus, seizure frequency was determined by 24/7 video/EEG monitoring for a period of four weeks. Following EEG recording, animals were sacrificed and percentage of newly-generated granule cells exhibiting abnormal morphologies was determined using confocal microscopy. Abnormal structures examined included basal dendrites, ectopic somata and mossy fiber axon sprouting. Results: Epileptic animals exhibited considerable variability in mean seizure frequencies, ranging from 0.1 to 3.0 seizures/day. When seizure frequency was correlated with the percentage of abnormal cells in each animal, significant positive correlations were found with: 1) the number of hilar ectopic DGCs, 2) the amount of mossy fiber sprouting and 3) the extent of mossy cell death. Basal dendrites tended to be more common in animals with high seizure rates, but this effect did not reach signficance. Conclusions: These studies provide correlative evidence in support of the hypothesis that abnormal granule cells contribute to the development of epilepsy, but also indicate that other factors - particularly mossy cell loss - are likely important as well.