Determining the shared neuronal network mechanisms of focal epileptic discharges and impaired memory processing in temporal lobe epilepsy

ABSTRACT Memory impairment is a common and devastating comorbidity of temporal lobe epilepsy. The network mechanisms underlying memory impairments are poorly understood. Micro-electrode recordings from temporal lobe epilepsy patients reveal frequent focal epileptic discharges (FEDs) that are only detectable with invasive recordings. Preliminary studies performed in our laboratory in a chronic epileptic mouse model revealed that mice experience frequent FEDs while they performed a spatial working memory task. Intriguingly, FEDs occurred robustly at specific locations on the maze, where healthy hippocampus normally generates population activity (sharp wave ripples, SWR) necessary for working memory. These data support the overall hypothesis that the cellular networks that normally partake in memory processes are hi-jacked by FEDs. We will test this hypothesis with three aims. For Aim 1 we will perform large scale tetrode recordings from freely moving mice to test the hypothesis that neurons active during FEDs overlap with neurons active during working memory SWR (wm-SWRs). For Aim 2 we will combine high-density linear probe recordings and chemogenetic inhibition to test the hypothesis that FEDs are generated in the CA3 region of the hippocampus. Finally, in the same animals as used in Aims 1 and 2, we will perform multi-day 24-hour recordings to test the hypothesis that FEDS occurring during working memory share cellular and network mechanisms with the early phase of behavioral seizures. The proposed research could help fill vital gaps in our knowledge about focal epileptic discharges – both in terms of their mechanisms and how they impact memory processing. We hope to elucidate which neurons participate in them, develop selective interventions to inhibit them, and determine how they impact behavioral seizures.