Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. We developed a novel conditioned seizure memory (CSM) paradigm, in which seizures and specific cues were paired. The CSM could be reliably retrieved, demonstrating a robust association. We also found that activation of cue-responding engram cells in hippocampus DG could create artificial CSM. After seizure memory retrieval, a protein synthesis-dependent reconsolidation process involving BDNF, mTOR and ERK pathways was observed. Pharmacological targeting of the reconsolidation process within a limited time window reduced seizures in animals and interictal epileptiform discharges (IEDs) in patients with refractory seizures. Altogether, our findings revealed an analogous process between memory and seizure, and supplied direct evidence on the new insight from physiological memory to understand pathological epilepsy as well as novel seizure-memory targeting strategy for the treatment of refractory seizures.