Seizure Susceptibility and Epileptogenesis in a Rat Model of Epilepsy and Depression Co-Morbidity

Abstract

Although a strong co-morbidity exists clinically between epilepsy and depression, the cause of this co-morbidity remains unknown, and a valid animal model is crucial for the identification of underlying mechanisms and the development of a screening tool for novel therapies. Although some rodent models of epilepsy have been reported to display behaviors relevant to affective disorders, the seizure susceptibility of animals prone to depression-like behavior has not been characterized. Toward this end, we assessed several forms of seizure sensitivity and epileptogenesis in rats selectively bred for vulnerability (Swim Lo-Active; SwLo) or resilience (Swim High-Active; SwHi) to depression-like phenotypes. The SwLo rats exhibit decreased motor activity in a swim test and other depression-like phenotypes, whereas the SwHi rats display increased motor activity in a swim test. SwLo rats exhibited a decreased latency to limbic motor seizures following acute pilocarpine administration in the absence of differences in pilocarpine pharmacokinetics, and also had a decreased threshold to tonic seizures induced by electroshock. Approximately half of the SwLo rats, but none of the SwHi rats, had spontaneous limbic motor seizures 5 weeks following pilocarpine-induced status epilepticus. While the number of stimulations required to achieve full amygdala and hippocampal electrical kindling were similar in the two rat lines, SwLo rats had a lower final hippocampal kindling threshold and more wet dog shakes during both amygdala and hippocampal kindling. Combined, these results indicate that SwLo rats are a model of epilepsy and depression co-morbidity that can be used for investigating underlying neurobiological and genetic mechanisms and screening novel therapeutics.

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…Animal models support a potential role of pathogenic mechanisms of mood disorders in the development of epileptic seizures and epileptogenesis (Kanner et al, 2014). Depression and manic episodes are described in bipolar disorder and in epilepsy (Kudo et al, 2001;Epps et al, 2012) underlining a bidirectional relationship. Manic attacks in dogs seem to resemble epileptic seizures (Phillips, 2005).…”

Rhythm and blues: Animal models of epilepsy and depression comorbidity

“…However, rapid kindling of the ventral hippocampus increased immobility in the FST and decreased saccharin preference, suggestive of a depressive-like phenotype [34]. While we did not see any differences in the rate of amygdala or hippocampal kindling in the SwLo model of depression, these rats did show a profound increase in wet dog shake seizure behaviors during kindling [27]. Combined, these findings suggest that the timing of stimulations, as well as the behavioral endpoint, are important modulators of depression-related behaviors and kindling.…”

“…A number of studies reported more immobility in the FST several weeks after pilocarpine-induced SE in rats [20–26]; researchers also saw a decrease in saccharin preference (when assessed), a further indication of a depression-and anhedonic-like phenotype in these epileptic rats. SwLo rats also demonstrated increased susceptibility to both acute pilocarpine-induced seizures and the appearance of spontaneous seizures 5 weeks following pilocarpine-induced SE [27]. …”

“…We recently confirmed this by showing that SwLo rats exhibited decreased latency to pilocarpine-induced seizures, as well as increased spontaneous seizures, following pilocarpine-induced SE. When assessed in electrical seizure-induction paradigms, the SwLo rats had a decreased threshold to ICES-induced seizures and differences in certain parameters of the kindling paradigm [27]. Interestingly, the amygdala and hippocampal kindling rates were not altered in SwLo rats, but they had a decreased stimulation threshold and displayed more wet dog shake seizure behavior during kindling.…”

“…Interestingly, carbachol can also be used to kindle motor seizures, and the wet dog shaking behavior associated with carbachol kindling may have muscarinic mechanisms [59]. In the SwLo rat, wet dog shaking was elevated during both hippocampal and amygdala kindling, pointing to possible muscarinic dysfunction in this model [27]. Combined, these findings suggest that muscarinic dysfunction in general may have opposing effects in partial and absence comorbidity models.…”