Abstracts

Rationale: Patients with epilepsy often experience cognitive impairments and although seizures contribute to this impairment, interictal discharges have been shown to transiently disrupt cognition. Interictal spikes (IS), brief high-amplitude waveforms that occur between seizures, are generally observed during quiet and motionless behavior or in non-REM sleep. Importantly, it is suggested that these specific periods are of crucial importance in terms of memory consolidation. When a rat explores its environment, hippocampal place cells discharge when the animal enters a specific region of the environment called a place field. Immediately after the rat stops, the place cells that were activated in this sequence fire in reverse order than they did originally during exploration, on a compressed time scale. This replay is observed synchronously with normal, high amplitude waveforms called sharp waves. Since IS occur during the same EEG states as sharp waves, we hypothesize that IS affect memory performance by disrupting hippocampal replay. Methods: Two behavioral conditions (linear track and modified T-maze) were used to assess place cells in two separate groups of 6 Sprague Dawley rats. On the linear track the rat had to navigate from one food well to the other, located on opposite ends of the track. In the second task the animal had to alternate between two opposing arms of the modified T-maze. Following training on either task rats were implanted with a microdrive-array electrode consisting of eight individually drivable tetrodes and an infusion cannula just above the CA1 layer of the right hippocampus. Following recovery from surgery, half the animals were infused with pilocarpine (0.5mg/ml, 1.5-2ul) to induce chronic epilepsy. The activity of place cells was then recorded in both behavioral apparatuses during task performance. Results: Replay was observed in control rats during periods of quiet behavior in both tasks (the delay period in the modified T-maze task and during food consumption in the linear track). For treated animals, 8-15 days after induction of status epilepticus, IS were seen in the right hippocampus and spontaneous seizures developed 2-3 days thereafter. IS occurred in EEG states that would normally be concurrent with replay in controls. However, if IS occurred 1-2 seconds before the onset of a sharp wave, place cell replay was disrupted. The integrity of the sequence was unaffected when IS were previously absent to sharp wave onset. Conclusions: Here we propose a mechanism of transient cognitive impairment due to IS, in which hippocampal replay becomes disordered following a spike. Our results suggest that IS impair memory processing by disrupting replay normally observed during sharp waves. While further analyses are required to directly link disrupted replay to aberrant performance in these tasks, these results provide a plausible mechanism by which IS impair cognitive processes. This work was supported by NIH Grant RO1NS056170.