Abstracts

Rationale: Depression is the most common psychiatric comorbidity in epilepsy and is still under-recognized and diagnosed. There is a bidirectional relationship between epilepsy and depression as a person with epilepsy has a 5-fold higher than average risk to develop depression, while epilepsy is about 5-fold more frequent in individuals with a history of depression. There is a connection between these two diseases yet the evidence for a shared pathology is not entirely clear. We aim to characterize seizure susceptibility and age- and sex-dependent depressive-like behavior in rats selectively bred for over 70 generations for immobility in forced swim test, while also examining the effect of rearing environment on animals’ genetic predisposition to depressive behavior. Methods: Sprague Dawley (SD) rats from Charles River Laboratories have been selectively bred for low activity scores (AS) in the Porsolt Forced Swim Test (FST) for 70 generations. The FST measures learned helplessness as they struggle to escape or give up and float for 15 minutes. We subtracted the amount of time an animal spends struggling from the amount of time an animal is immobile to give an AS. We performed 3 experiments: (1) FST at various postnatal (P) ages:  P30 (n=11), P35 (n=8), P42 (n=44) and P90-120 (n=16). (2) Seizure occurrence to intraperitoneal kainic acid (KA, 20mg/kg) injection at P35.  SwLo rats (n=16) were compared to SD rats (n=16) purchased from Charles River. (3) Differential environments post-weaning (P21) followed by FST activity scores at P42. The three different environments consisted of isolated (n=13), group housed (n=15, 2-3 rats/cage), and enriched (n=16, 8 female or 8 male rats together in a large box with access to toys a running wheel).  Results: At P30, SwLo showed positive activity score (AS) similar to random control SD.  Already at P35, SwLo started to show negative AS and spent more time immobile than active (p < 0.01). By P90, naïve SwLo rats, without any further treatment, became nearly immobile in the FST as seen previously (p < 0.001)(Fig. 1). At P35, 88% (14/16) of SwLo experienced convulsive seizures whereas only 38% (6/16) of SD control rats had overt seizures (Fisher’s exact test, p < 0.01).We tested for the therapeutic efficacy of enriched environment (P21-P42) to reverse the immobility in SwLo at P42. Enriched environment not only failed to improve immobility, but worsened. This was almost exclusively due to significantly increase immobility in female SwLo rats (n=8/group, t-test vs. isolated, p < 0.0001). Isolation had little effect on FST phenotype (Fig 2). Conclusions: Depressive behavior in SwLo rats developed over time becoming evident by 5 weeks of age (P35). At P35, these animals also exhibited increased susceptibility to KA-induced seizures. Most surprising was the effect of 3 weeks of environmental enrichment.  There was clear sexual dimorphism noted at P42. Significant worsening depressive behavior was observed exclusively in female rats while post-weaning environment had little effect on male animals’ FST activity scores.  The reason why the enriched environment had a worsening of phenotype effect on females is unknown. We speculate that female animals with a predisposition to depression may have heightened stress, when a large group is forced to interact with each other. Funding: Supported by NIH/NINDS R01 NS073768