Abstracts

RATIONALE: Temporal lobe epilepsy has been linked to a loss in temporal lobe volume (Bothwell et al., 2001; Bertram et al., 1990). However, whether this loss of volume is a cause or consequence of seizures remains unknown. Seizure-prone and seizure-resistant rat strains have been developed through selective breeding of rats with fast and slow amygdala kindling rates, respectively. Interestingly, in addition to creating differences in seizure susceptibility, the natural breeding process also produced differences in limbic structure volume. Specifically, seizure-prone rats show reduced dorsal hippocampal and temporal lobe volumes relative to seizure-resistant rats. This finding suggests that differences in temporal lobe volume are indeed heritable and are not merely a consequence of neuronal damage following repeated seizures. Accordingly, genetic factors that influence the formation of the hippocampus and its basal operation may predispose that structure to seizure. The identification of differences in constitutive gene expression within the naive hippocampii of seizure-prone and seizure-resistant rats may, therefore, reveal mechanisms underlying seizure susceptibility.
METHODS: To screen for differences in constitutive gene expression between the strains, we probed 1.7K microarrays with flourescently-labelled cDNAs derived from the hippocampii of na[iuml]ve seizure-prone and seizure-resistant rats. Differential gene expression isolated using this screening technique was verified using several molecular biological tools including QPCR and in situ hybridization.
RESULTS: A number of genes were found to be constitutively underexpressed in the hippocampii of na[iuml]ve seizure-prone rats relative to na[iuml]ve seizure-resistant rats. These genes included ubiquitin protein ligase, P53, mGluR4 and a number of genes involved in fatty acid synthesis and metabolism. Surprisingly, only one of the 1700 genes probed on the microarray was found to be overexpressed in the hippocampii of seizure-prone animals, namely the thyroid hormone binding protein transthyretin.
CONCLUSIONS: The finding that the majority of genes differentially expressed between the strains are underexpressed in the seizure-prone hippocampus may suggest a loss of one or more cell populations that would normally contribute to seizure resistance. On the other hand, it may be that the selective downregulation of these genes throughout the hippocampus plays a crucial role in seizure susceptibility. Further understanding of a common thread between the genes identified may help to resolve this issue.
[Supported by: CIHR]