Early Increases in Hippocampal Synchrony Predict Chronic Epileptiform Burden in a Temporal Lobe Epilepsy Model

Abstract

Temporal lobe epilepsy (TLE), the most common focal epilepsy, is often drug-resistant and arises predominantly in the hippocampus. Disease severity is conventionally assessed by seizure frequency and duration, yet epileptiform activity outside discrete seizures may also track disease progression. Whether this activity reflects hippocampal network reorganization as part of epileptogenesis, and whether such reorganization predicts chronic severity, is unknown. Here, we combined longitudinal two-photon calcium imaging of hippocampal CA1 neurons with repeated 24-hour EEG recordings that quantified epileptiform burden in the same pilocarpine treated mice over 16 weeks. CA1 firing and synchrony rose acutely, subsided during a latent period, and increased again chronically, with synchronized firing organized into brief waves that propagated in a consistent direction. Epileptiform burden followed a similar temporal trajectory and increasingly contained electrographic seizures. CA1 synchrony correlated with epileptiform burden and stratified mice into groups with distinct neuronal and electrographic outcomes. CA1 synchrony measured within three weeks of pilocarpine induction predicted chronic epileptiform burden, identifying early hippocampal synchrony as a candidate imaging biomarker and pointing to an early window for intervention in TLE.