Abstracts

Rationale: Epilepsy causes dramatic cell death and reorganization of interneuron circuits in both humans and rodent models. We hypothesized that this is likely to cause profound deficits in hippocampal interneuron synchronization to ongoing theta and gamma oscillations in epileptic mice. Furthermore, because interneurons route the flow of contextual information through the hippocampus, we hypothesized that circuit dysfunction would lead to altered place cell dynamics and reduced stability of place fields over several days.Methods: To test these hypotheses we first trained both pilocarpine-treated and control mice to run through a virtual linear track to receive a water reward while head-fixed atop a Styrofoam ball floating on compressed air. We then used high density silicon probes with 128 recording sites to simultaneously record single units and local field potentials throughout dorsal CA1 and dentate gyrus while mice ran through the virtual linear track. In addition, to monitor the stability of place cells over several days to weeks, we designed and built a miniature microscope to image calcium signals in freely behaving animals. We trained both pilocarpine-treated and control animals to run along a real linear track for water reward and imaged the same population of cells in CA1 over several weeks.Results: Pilocarpine-treated epileptic animals showed reduced gamma power in dentate gyrus as well as reduced theta and gamma coherence between CA1 and dentate gyrus indicating reduced synchronization between these regions. We also found a reduction in theta-gamma cross-frequency coupling in epileptic animals. We further examined this synchronization deficit by examining the phase-locking of dentate gyrus interneurons to ongoing theta oscillations and found that while the magnitude of phase-locked firing in individual dentate gyrus interneurons was comparable to control animals, the preferred phase of these cells as a group was more dispersed and shifted to a later phase of theta. In addition, using our miniature microscopes we have found preliminary evidence of reduced precision of place cell firing and reduced stability of place fields over several days.Conclusions: Together, these findings indicate a clear desynchronization between dentate gyrus and CA1 regions of the hippocampus of epileptic mice. These circuit-level changes may contribute to cognitive deficits in chronic epilepsy. Future studies will gauge the efficacy of interneuron replacement therapies on restoring synchrony in dentate gyrus and CA1, as well as the dynamics and stability of place cells in CA1.