Abstracts

Rationale: Epilepsy causes dramatic cell death and reorganization of interneuron circuits in both humans and rodent models but the consequences of these changes on hippocampal processing remain unknown. Methods: We used silicon probes to record single units and local field potentials throughout dorsal CA1 and dentate gyrus in head-fixed epileptic and control mice running through a virtual linear track. We further examined contextual information processing in these animals by recording CA1 place cells in epileptic and control mice using custom-made head-mounted miniature microscopes to image calcium transients in large populations of CA1 neurons as animals ran across a real-world linear track over several days. Finally, we transplanted embryonic interneuron precursors from the medial ganglionic eminence (MGE) into the hippocampus and are testing whether these transplants, which rescue seizures and cognitive deficits in epileptic mice, can also rescue the electrophysiological and contextual processing deficits observed in epileptic mice. Results: We found dramatic alterations of hippocampal synchronization in chronically epileptic mice, at least two months after pilocarpine-induced status epilepticus. Epileptic mice had reduced theta and gamma power and coherence, altered cross-frequency coupling, and altered phase preferences to ongoing theta oscillations. In particular, dentate hilar neurons had a similar magnitude of theta phase modulation of their firing rate, but the preferred phase of these cells as a group was more dispersed and shifted to a later phase of theta. We also found that place fields in chronically epileptic mice were larger and contained less spatial information than in control mice. Conclusions: Together, these findings indicate a significant desynchronization within and between the CA1 and dentate gyrus regions of the hippocampus that may lead to cognitive dysfunction in chronically epileptic mice. We predict that transplantations will restore specific deficits in hippocampal synchronization and place cell dynamics reflecting rescue of hippocampal processing. Funding: Epilepsy Foundation Postdoctoral Fellowship (TS), T32 NS007101-33 Training Grant on Cellular Neurobiology from NINDS (TS), NIMH Grant 1R01DA034178 (PG), NIH Grant U01NS094286 (PG), VA Merit Award - Peyman Golshani, DGSOM Dean of Research Fund and Departmental Funds - Peyman Golshani, NIMH Grant RO1MH101198 (SM)