Altered theta coupling between medial entorhinal cortex and dentate gyrus in temporal lobe epilepsy

Purpose: Temporal lobe epilepsy is often accompanied by neuron loss and rewiring in the hippocampus. We hypothesized that the interaction of subnetworks of the entorhinalhippocampal loop between epileptic events should show significant signatures of these pathologic changes. Methods: We combined simultaneous recording of local field potentials in entorhinal cortex (EC) and dentate gyrus (DG) in freely behaving kainate-injected mice with histologic analyses and computational modeling. Key Findings: In healthy mice, theta band activity was synchronized between EC and DG. In contrast, in epileptic mice, theta activity in the EC was delayed with respect to the DG. A computational neural mass model suggests that hippocampal cell loss imbalances the coupling of subnetworks, introducing the shift. Significance: We show that pathologic dynamics in epilepsy encompass ongoing activity in the entorhinal-hippocampal loop beyond acute epileptiform activity. This predominantly affects theta band activity, which links this shift in entorhinal-hippocampal interaction to behavioral aspects in epilepsy.