Abstracts

Rationale: A consistent histological finding in temporal lobe epilepsy (TLE) is “dispersion” of the granular cell layer of the hippocampus. This is also seen in animal models along with a stereotypical pattern of neuronal loss in other hippocampal subfields. Enhanced neurogenesis is also seen in the granular cell layer, however it is unknown whether these new cells simply replace cells lost during the epileptogenic process or represent an excessive proliferative response. The phenomenon of granule cell dispersion potentially biases investigation of this by increasing the volume of the dentate gyrus. To circumvent this limitation, we have used unbiased stereological methods to quantitate the total number of cells in the dentate granular cell layer in the post-kainic acid (KA) status epilepticus (SE) rat model of TLE. Methods: 13-week old male wistar rats were treated with KA (2.5-5 mg/kg i.p.) to induce SE (n=9). Control animals received saline (n=15). Animals were transcardially perfused five weeks post SE (or saline administration) and their brains prepared for cryo-sectioning. Stereological estimates of total neuronal numbers and the width of the supra- and infra-pyramidal blades of the dentate gyrus were determined from thionin stained sections. Immunohistochemical analysis of synaptophysin expression in the dentate gyrus were also conducted to assess synaptogenesis in this region. Results: A significant increase in the width of the suprapyramidal blade of the dentate gyrus was observed in epileptic animals confirming the presence of granule cell dispersion in this model of TLE. The total number of dentate granule cells was significantly increased in the epileptic animals compared to controls (1.35x106 Vs. 1.04x106, p<0.01). In contrast the total number of CA1 pyramidal cells was decreased in the epileptic rats (2.56x105 Vs. 3.5x105, p<0.05). Synaptophysin expression was increased in the dentate gyrus, with a trend for positive correlation between dentate granule cell number and synaptophysin expression in the dentate hilus (R2=0.49, p=0.05). Conclusions: In addition to the previously recognized CA1 pyramidal cell loss and granular cell “dispersion” in the post-KA SE rat model, there is an increase in total granule cell number. This suggests that neurogenesis in this region is not just compensating for lost neurons, but rather reflects an aberrant proliferative response that potentially has pathogenic significance.