That Sync-ing Feeling: The Progressive Drop of Hippocampal and Entorhinal Coordination in Murine Epilepsy

Distinct Changes to Hippocampal and Medial Entorhinal Circuits Emerge Across the Progression of Cognitive Deficits in Epilepsy Feng Y, Diego KS, Dong Z, Christenson Wick Z, Page-Harley L, Page-Harley V, Schmipper J, Lamsifer SI, Pennington ZT, Vetere LM, Philipsberg PA, Soler I, Jurkowski A, Rosado CJ, Khan NN, Cai DJ, Shuman T. Cell Rep . 2025;44(2):115131. Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in the hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within the MEC and between HPC and MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.