Abstracts

Rationale: Temporal lobe epilepsy (TLE) represents ~20% of all diagnosed epilepsy syndromes and frequently involves cognitive comorbidities such as memory loss. Currently, there are no therapies that treat both seizures and cognitive deficits. We hypothesized that theta-frequency stimulation (7.7 Hz or theta burst) of the medial septal nucleus (MSN) early in the course of the disease would entrain hippocampal oscillations and alter the course of epileptogenesis in pilocarpine-treated rats, resulting in lasting improvements in cognitive outcome and increasing seizure threshold. Methods: Adult male Sprague-Dawley rats were implanted with bipolar stimulating electrodes in the MSN, in addition to recording electrodes in dorsal and ventral hippocampus, prefrontal cortex, and MSN. Baseline EEG was recorded prior to induction of seizures. Two weeks after implantation, animals were selected randomly for sham or pilocarpine (1 mg/kg scopolamine methyl nitrate followed by 350 mg/kg pilocarpine 0.5 hr later; 8 mg/kg diazepam 4 hr post-pilocarpine). Pilocarpine rats were counterbalanced into stimulation groups: no-stimulation, fixed theta (7.7 Hz, 80 µA), or theta burst (50 ms trains of 200 Hz, 7.7 trains per second, 50 µA). Starting on post-pilocarpine day 4 (PPD 4), rats received 30 minutes of daily stimulation for 13 days. Time-matched EEG was recorded in non-stimulation rats. Animals underwent behavioral testing with concomitant EEG recording on PPD 32, 43-54, 56 (Barnes maze, novel object, and flurothyl). Results: Compared to shams, no-stimulation pilocarpine-treated animals demonstrated increased escape latency (p < 0.05) and greater use of random search strategy (pk means clustering analysis sorted epileptic animals into low and high spike groups at a threshold of 2.5 IIS/min.  Approximately 92% of no-stimulation animals were in the high-spike cluster, as opposed 50% of fixed theta animals and 27% of theta burst animals. When behaviors were re-analyzed by spike rate, animals with =2.5 IIS/min performed significantly worse on both the Barnes Maze.  Conclusions: Pilocarpine impairs cognitive performance and lowers seizure threshold, and theta-frequency stimulation of the MSN significantly improves outcome across these behaviors.  Interestingly, in the majority of rats, stimulation reduced IIS compared to pilocarpine controls. In conclusion, early intervention has the potential to improve both seizure threshold and cognition in pilocarpine-treated rats. Funding: Not applicable