Abstracts

Rationale: The bi-directional co-morbidity between epilepsy and depression is likely due to similarities in neurobiological pathways and/or genetic influences, and is linked with decreased success of treatment. A valid animal model is essential for identifying the underlying mechanisms and developing novel therapeutics for this co-morbidity. Swim Lo-Active (SwLo) rats are a selectively-bred model for depression-susceptibility based on their phenotype on the forced swim test. We hypothesized that if the same genes govern both depression-susceptibility and seizure susceptibility, then SwLo rats should also be more susceptible to seizures. Previous research indicated that SwLo rats have increased mortality following kainic acid-induced seizures, suggestive of increased sensitivity. This study seeks to further validate the SwLo rats as a model of co-morbid epilepsy and depression and characterize the genes involved in the co-morbidity. Methods: Swim Lo-Active (SwLo) and Swim Hi-Active (SwHi) rats were selectively bred for decreased and increased struggling in the forced swim test (FST) to create models of depression-susceptibility and resiliance, respectively. To assess seizure susceptibility, 380 mg/kg pilocarpine was administered i.p. and latency to motor seizure was measured. A second group of rats was assessed for electroshock-induced seizures using an increasing current electroshock (ICES) paradigm, allowing for determination of seizure threshold in individual rats. To identify candidate genes that may underlie this co-morbidity, we subjected hippocampal samples from five additional SwLo and SwHi rats to expression microarray analysis. Results: We found that SwLo rats had higher sensitivity to pilocarpine- and electroshock-induced seizures compared with SwHi rats, validating these animals as a model of epilepsy and depression co-morbidity. Following administration of pilocarpine, SwLo rats showed a significant decrease in latency to motor seizure compared to SwHi rats (19.73 min vs 55.09 min, t(20)=3.528, p=0.0021). Using the ICES paradigm, we determined that SwLo rats are indeed more susceptible to electrically-induced seizures than SwHi rats, as shown by a comparison of the threshold stimulation required to induce tonic flexion (13.83 mA vs. 17.33 mA, t(10)=9.391, p<0.0001). Additionally, we found 210 genes that exhibited significantly different expression between the rat lines (fold change >2). Of these 210 genes, 121 had higher expression in the SwHi rats than the SwLo, while 89 genes showed higher expression in SwLo rats. Of particular interest were the genes Gabbr1, Gabrb2, and COMT (SwHi > SwLo), Hcn1 and Kcnj10 (SwLo > SwHi), which will be further characterized by RT-PCR and Western blotting. Conclusions: These studies demonstrate the utility of SwLo rats as a model of co-morbid epilepsy and depression and provide potential candidates for novel therapeutics.