Abstracts

Rationale: Status epilepticus (SE) is associated with the development of epilepsy and comorbidities, including deficits in cognition. Several studies have implicated the increased activation of the mammalian target of rapamycin (mTOR) signaling cascade in the pathophysiology of SE and epilepsy and aberrant memory processing. Recently, we showed that mTOR inhibition during epileptogenesis (2-3 weeks after SE) reduced hyperactive mTOR signaling and rescued memory deficits when tested at the time of treatment. However, it is not known whether this early treatment has long-term effects on memory when animals are epileptic. Therefore, in this study we evaluated the longevity of early mTOR inhibition on the memory of epileptic animals. We also tested whether mTOR inhibition can rescue memory deficits in animals in which epilepsy has already developed. Methods: SE was induced in rats using pilocarpine (Pilo) while controls (Sham) received saline. The mTOR inhibitor rapamycin (Rap) or vehicle (Veh) was given every other day for one week 2-3 weeks after SE induction. The treatment groups from both were: Sham+Veh; Sham+Rap; Pilo+Veh; and Pilo+Rap (n=8-12 per group). One month after SE, animals were monitored weekly to screen for spontaneous recurrent seizures (SRS). Animals were then tested in the Morris Water maze (MWM) and Novel Object Recognition (NOR) to evaluate spatial memory and Open Field (OF) to screen for locomotor deficits. After behavioral testing was completed, we performed western blotting to evaluate mTOR pathway activity using an antibody against S6 phosphorylated at S240/244. Results: All Pilo animals included in behavioral tests exhibited SRS. Early Rap treatment did not reduce seizure activity (p-value not significant). Pilo+Veh rats exhibited significantly longer escape latencies during the acquisition phase in MWM and decreased time spent in the target quadrant compared to Sham+Veh animals (p< 0.05 and p<0.01, respectively). In NOR, Pilo+Veh animals displayed no preference for the novel object as compared to controls (p<0.001). In the Pilo+Rap group when tested during Rap treatment at the 3 week post-SE time point, the deficits in MWM and NOR were rescued to Sham+Veh performance levels. When tested 5 months after SE, early Rap treatment did not rescue the deficits in MWM or NOR in the Pilo animals (p-values n.s. for Pilo+Veh compared with Pilo+Rap). For all behavioral tasks, Rap had no effect on Sham animals.Conclusions: These data suggest that aberrant mTOR signaling contributes to deficits in hippocampal-dependent spatial learning and memory. Future studies are planned to evaluate whether late Rap treatment rescues these deficits in epileptic animals, particularly since the early treatment is not long lasting.