Beyond the Focus: The Piriform-Entorhinal-Dentate Circuit as a Driver of Network Hyperexcitability in Epilepsy

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

Yan Tao, Yuxin Zhao, Wenqi Zhong, Jiajia Zhang, Hongyan Zhu, Xutao Zhu, Zikun Wang, Na Wang, Liqin Yang, Fuqiang Xu, Ruiqi Wu. PLoS Biol. 24(2): e3003577 (2026).

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.