Age-related behavioral, morphological and physiological changes in the hippocampus of zitter rats

Convulsive seizure is known to be associated with hippocampal abnormalities, such as hilar cell degeneration, abnormal mossy fiber sprouting in the dentate gyrus (DG) and abnormal expression of immediate early genes. However, whether these morphological changes are a cause or consequence of convulsive seizures has remained contentious. Zitter (zi/zi) rats carry a mutation of the attractin gene and display spongiform degeneration of the brain. Spontaneous convulsive seizures in zi/zi rats over 8 months (M) old were demonstrated using 24-h video monitoring. Spontaneous convulsive seizures did not occur before this age. The present study examined structural changes in the hippocampus of zi/zi rats at different ages. Fluoro-Jade B-positive cells first appeared in the hilus of 1-M zi/zi rats, indicating hilar cell degeneration. After 2 M, mossy fiber sprouting was observed in granular cell layers and in the inner molecular layer. After 10 M, granule cells showed Fos expression. In the hippocampal slices from 12-M zi/zi rats, abnormal population spikes in the DG were observed in the presence of bicuculline and strychnine. Conversely, Sprague-Dawley rats showed no aberrant zinc distribution, few Fos-positive cells, no Fluoro-Jade B-positive cells in the hippocampus and no abnormal population spikes in the DG. These data indicate that morphological changes in the hippocampus might contribute to epileptogenesis in this mutant rat.