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.

Figure 1

SwLo rats have a shorter latency to pilocarpine-induced seizures than SwHi rats that is independent of pilocarpine pharmacokinetics. (a) SwLo (n=11) and SwHi (n=11) rats were injected with atropine methyl bromide (2 mg/kg, i.p.), followed by pilocarpine (380 mg/kg, i.p.) 30 min later, and latency (mean±SEM) to limbic motor seizures was measured. ^*p<0.01 compared with SwHi rats. (b) SwLo (n=3) and SwHi (n=3) rats were treated with atropine and pilocarpine as above, euthanized 5, 10, or 15 min later, and hippocampal pilocarpine levels (mean±SEM) were measured by HPLC.

Figure 2

SwLo rats are more susceptible to electrically induced seizures than SwHi rats. Increasing current was delivered via earclip electrodes to SwLo and SwHi rats (n=6 per group), and threshold stimulation required to induce tonic hind limb flexion was recorded. ^*p<0.0001.

Figure 3

Kindling parameters in SwLo and SwHi rats. SwLo and SwHi rats (n=6–10 per group) were implanted with electrodes in the amygdala or hippocampus. Initial electrographic seizure threshold was determined, and threshold stimulations were delivered twice per day until rats reached a fully kindled state, defined as three consecutive rearing/falling seizures. Shown are the mean±SEM of initial and final threshold used to induce an electrographic seizure during amygdala (a) and hippocampal (b) kindling, the number of wet dog shakes during amygdala (c) and hippocampal (d) kindling, and the number of stimulations required to reach a fully kindled state in the amygdala (e) and hippocampus (f). ^*p<0.05, ^***p<0.0001 compared with SwHi rats, ^#p<0.01 compared with initial threshold for that rat line.