Abstracts

Rationale: Wistar audiogenic rat (WAR) is a genetic animal model susceptible to audiogenic seizures. When exposed to high intensity auditory stimulus (110 dB) rats from this strain develop tonic clonic generalized seizures followed by clonic spasms. Brain structures thought to be involved in these acute audiogenic seizures are the inferior and superior colliculus, substantia nigra, reticular formation and periaquedutal grey matter. The aim of this study was to determine molecular pathways involved in the susceptibility to seizures in these model using gene expression analysis. Methods: We obtained total RNA from five susceptible WAR [hippocampus and corpora quadrigemina (IC and SC)], five control Wistar and five WAR-naive (WAR prior to auditory stimulus). Gene expression analysis was performed using microarray technology, and analyzed in R environment using the Affy and RankProd packages from Bioconductor, as well as the MetaCore® platform to identify molecular networks, gene ontology categories and gene interactions. Genes with differential expression and a possible biological role in epileptogenesis were validated by qRT-PCR. Results: In WAR, expression profile showed a total of 1624 differentially expressed transcripts in the corpora quadrigemina and 1351 differentially expressed in the hippocampus compared with controls, with 616 upregulated and 1008 downregulated in corpora quadrigemina and 660 upregulated and 691 downregulated in the hippocampus. Enriched gene ontology categories identified in WAR were involved in oxidative phosphorylation and neurophysiological process GABA-A receptor life cycle. Genes validated by qRT-PCR were Grin1, Nedd8, Il18 and Slc1a3. Subsequently, we compared expression of gene validated by qRT-PCR among the three groups of animals, WAR, WAR-naive, and Wistar, and observed that overall these genes were downregulated in WAR-naive. Conclusions: Our results show that auditory stimulus was able to modify basal expression of several genes analyzed, thus activating specific gene pathways such as oxidative phosphorylation and neurophysiological process GABA-A receptor life cycle, which are likely to be involved in the susceptibility to seizures in WAR.