Piriform seizures mediated by the piriform-entorhino-dentate circuit induce brain-wide functional reorganization in mice

Systematic identification of global epileptic reorganization and critical seizure-controlling circuits is essential for comprehending epilepsy pathophysiology and for developing network-guided targeted therapies. The piriform cortex (PC) is a recognized epileptogenic region, but how its hyperactivity reshapes whole-brain dynamics and which specific circuits mediate seizures remains unclear. Through multimodal integration of optogenetics, fMRI, electrophysiology, Ca2+ imaging, neural tracing, and circuit-specific manipulation, we mapped the whole-brain dynamics following optogenetic stimulation of PC and identified the fundamental circuit governing piriform seizures. We observed pronounced generalized seizures in mice via repeated optogenetic stimulation of PC Vglut1+ neurons. Optogenetic kindling of PCVglut1 induced widespread blood-oxygen-level-dependent (BOLD) signal hyperactivation and resting-state functional connectivity (rsFC) alterations, notably sustained hyperactivation in the lateral entorhinal cortex (Lent) and enhanced PC-Lent rsFC. Chronic elimination of Lent neurons receiving PC projections significantly decreased the Lent-dentate gyrus (DG) rsFC. Disruption of the PC-Lent or Lent-DG circuit effectively suppressed PC-stimulation-triggered seizures and brain-wide hyperactivation. Our findings demonstrate the dominant role of the PCVglut1-Lentglut-DG circuit in mediating piriform seizures and driving their resulting brain-wide functional reorganization, offering new insights for targeted epilepsy treatments.