Abstracts

Rationale: Status epilepticus (SE) is associated with the development of epilepsy and comorbidities, including deficits in cognition and social behavior. Previous studies have implicated the mammalian target of rapamycin (mTOR) signaling cascade in the pathophysiology of SE and epilepsy using the mTOR complex 1 (mTORC1) inhibitor rapamycin (Rap). Under basal conditions, mTORC1 regulates protein synthesis and is an important mediator of synaptic plasticity. However, whether aberrant mTOR signaling contributes to behavioral deficits following SE is unclear. In the studies reported here, we determined whether aberrant mTORC1 signaling plays a role in hippocampal-dependent learning and memory tasks, social behavior, locomotion, and anxiety. Methods: SE was induced in rats using pilocarpine (SE) while controls (Sham) received saline. Two weeks after SE induction, we administered Rap or vehicle (Veh) every other day for one week. The treatment groups were Sham + Veh, Sham + Rap, SE + Veh, and SE + Rap (n=7-12 per group). We tested SE and Sham animals (from each treatment group) in the Morris Water maze (MWM), Novel Object Recognition (NOR), Social Interaction (SI), and the Open Field task (OF) tasks. After behavioral testing was completed, we performed western blotting to verify inhibition of mTORC1 (S6 phosphorylated at S240/244). Results: SE + Veh rats exhibited significantly longer escape latencies during the acquisition phase in MWM test and decreased time spent in the target quadrant searching for a hidden platform in the probe trial compared to Sham + Veh animals (p< 0.05 and p<0.01, respectively). In NOR, SE + Veh animals displayed no preference for the novel object as compared to controls (p<0.001). In the SE + Rap group, the deficits in MWM and NOR were rescued to performance levels of Sham + Veh animals. In SI task, SE + Veh animals spent less time with a social partner than Sham + Veh animals (p<0.05). Locomotor activity in the OF revealed that SE + Veh rats spent more time in the inner portion of the OF arena than Sham + Veh and displayed increased distance traveled and travel velocity (p<0.05). In the SE + Rap animals, neither the time spent with a social partner in SI nor the travel distance or velocity in OF were rescued. For all behavioral tasks, Rap had no effect on Sham + Rap animals. Conclusions: These data suggest that aberrant mTORC1 signaling contributes to deficits in hippocampal-dependent learning and memory but not aberrant social behavior following SE. Future studies are planned to evaluate whether inhibition upstream in the mTOR pathway to target both mTORC -1 and -2 will rescue both learning and memory and social behavior deficits following SE.