Deficits in behavioral time-scale plasticity underlying imprecision and instability of hippocampal cognitive representations in temporal lobe epilepsy

About This Grant

Project Summary Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults and is associated with cognitive deficits that can prevent individuals from working and living independently. Yet, because the mechanisms leading to cognitive disability from TLE are still poorly understood, there are currently no effective treatments. In hippocampus, a brain structure critical for memory, pyramidal neurons fire at specific locations in space, creating a cognitive map of the environment. We have recently discovered that TLE model mice have a strong reduction in precision, reliability, and day-to-day stability of spatial representations in the hippocampus. Yet the mechanisms that lead to place cell imprecision and instability in hippocampal CA1 region remain poorly understood. Discovering these mechanisms could help with future discoveries of better treatments of cognitive difficulties in epilepsy. Recent work indicates that behavioral time-scale plasticity (BTSP) is a robust mechanism for single-trial generation of place-specific firing (place fields) after occurrence of single plateau potentials in CA1. BTSP may be the main mechanism for generation and remapping of place field maps. Yet, it is not understood whether BTSP is abnormal in TLE. Furthermore, our group has recently discovered that BTSP also occurs during the performance of non-spatial cognitive tasks, suggesting that dysfunctional BTSP could be a general mechanism driving cognitive dysfunction in TLE. We hypothesize that dysfunctional BTSP likely plays a dual role in the generation of imprecise and unstable place field maps. First, we hypothesize that plateau potentials will be less effective in generating robust place-related firing in TLE, resulting in imprecise place fields. Second, we hypothesize that the paroxysmal depolarizing shifts that are the intracellular correlates of epileptic spikes will aberrantly and repeatedly induce a weakened BTSP, resulting in repeated remapping of imprecise place fields. In Aim 1, using two-photon holographic optogenetics, we will test whether BTSP is more difficult to induce and results in less precise place fields in the pilocarpine model of epilepsy. In Aim 2 we will determine whether interictal spikes can induce a weakened form of BTSP resulting in rapid remapping of imprecise place fields. In Aim 3, we will determine if non-spatial BTSP during performance of a working memory task is also impacted in TLE. These experiments will allow us to focus in on a specific plasticity mechanism that can then be targeted in future experiments to improve cognition in TLE.