Abstracts

We have previously reported on a seizure-like syndrome (NIS-L) in adult rats treated with low doses of kainate agonists during postnatal development (postnatal days 8-14). NIS-L is characterized by reproducible behavioural sequelae reminiscent of a stage 2 seizure, that manifests on exposure to a novel environment.
Acute injections of high doses of kainic acid to adult animals, with subsequent status epilepticus, is a widely used model for temporal lobe epilepsy (TLE). Animals that survive injection subsequently develop spontaneous recurrent seizures weeks to months later. These animal models, as well as clinical TLE, are typically associated with specific anatomical changes in the hippocampus (eg. mossy fiber sprouting and cell loss).
The purpose of this study was to determine whether the treatment paradigm that induces NIS-L results in anatomical changes in the hippocampus that are similar to those seen in both conventional animal models and clinical temporal lobe epilepsy. Identifying and quantifying hippocampal anatomical changes in NIS-L animals is an important step in defining the utility and characteristics of what appears to be a unique developmental rat model of temporal lobe epilepsy. SD rats were injected daily with either saline or subconvulsive doses of the kainate agonists domoic acid (n= 9) or kainic acid (n= 9) from post-natal day 8-14. When the animals reached adulthood they where exposed to the Morris Water Maze and the incidence of the NIS-L syndrome was recorded. Hippocampal anatomy was then analyzed using Timm[rsquo]s Stain for mossy fiber sprouting, as well as cresyl violet staining for cell counts. Cell counts were performed in CA3 (a,b, and c), CA1 and the dentate gyrus. Mossy fiber sprouting was assessed in area CA3 and in the dentate gyrus, using a standard qualitative scale. Results indicated that drug treated animals reliably displayed the NIS-L syndrome (p[lt]0.01) whereas saline treated animals did not. Drug treated animals also had significantly increased dentate granule cell axon sprouting (mossy fiber sprouting) in the inner molecular layer of the dentate hilus (F= 3.96, p = 0.04), as well as in the stratum oriens of area CA3 (F= 5.68, p = 0.015). Treated animals also displayed significantly diminished cell counts in hippocampal areas CA1 (F= 4.7, p= 0.024), CA3b (F= 10.54, p= 0.001) and CA3c (F= 5.18, p= 0.017). These results confirm that perinatal injections of low doses of kainate agonists reliably produce a seizure-like syndrome (NIS-L) in adult rats, and demonstrate that this treatment paradigm also produces changes in hippocampal cytoarchitecture that are consistent with existing animal models of TLE. (Supported by Canadian Institutes of Health Research
Natural Sciences and Egineering Research Council of Canada
PEI Health Research Program)