Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy

• Published in: Cell reports (Cambridge) 2025-02, Vol.44 (2), p.115131, Article 115131
• Main Authors: Feng, Yu, Diego, Keziah S., Dong, Zhe, Christenson Wick, Zoé, Page-Harley, Lucia, Page-Harley, Veronica, Schnipper, Julia, Lamsifer, Sophia I., Pennington, Zachary T., Vetere, Lauren M., Philipsberg, Paul A., Soler, Ivan, Jurkowski, Albert, Rosado, Christin J., Khan, Nadia N., Cai, Denise J., Shuman, Tristan
• Format: Article
• Language: English
• Subjects: circuit desynchronization; CP: Neuroscience; electrophysiology; entorhinal cortex; epilepsy; hippocampus; spatial memory; theta oscillation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115131

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. [Display omitted] •Epileptic mice have progressive memory impairments dissociable from seizures•Early memory impairment is minor and associated with hippocampal desynchronization•More severe memory deficits are associated with reduced MEC-hippocampal synchrony•MEC3 neurons active at the trough of theta are uniquely impaired in epileptic mice Feng et al. demonstrate that memory deficits in temporal lobe epilepsy involve multiple discrete mechanisms with distinct time courses. In epileptic mice, early-onset memory deficits are associated with disrupted hippocampal synchronization, while more severe, late-onset impairments are associated with disrupted synchrony of medial entorhinal cortex circuits.