Interictal-period-activated neuronal ensemble in piriform cortex retards further seizure development

Epileptic networks are characterized as having two states, seizures or more prolonged interictal periods. However, cellular mechanisms underlying the contribution of interictal periods to ictal events remain unclear. Here, we use an activity-dependent labeling technique combined with genetically encoded effectors to characterize and manipulate neuronal ensembles recruited by focal seizures (FS-Ens) and interictal periods (IP-Ens) in piriform cortex, a region that plays a key role in seizure generation. Ca2+ activities and histological evidence reveal a disjointed correlation between the two ensembles during FS dynamics. Optogenetic activation of FS-Ens promotes further seizure development, while IP-Ens protects against it. Interestingly, both ensembles are functionally involved in generalized seizures (GS) due to circuit rearrangement. IP-Ens bidirectionally modulates FS but not GS by controlling coherence with hippocampus. This study indicates that the interictal state may represent a seizure-preventing environment, and the interictal-activated ensemble may serve as a potential therapeutic target for epilepsy.