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

## TL;DR

This study identifies a brain circuit linking the piriform cortex to seizures and widespread brain changes, offering new targets for epilepsy treatment.

## Contribution

The study reveals the piriform-entorhino-dentate circuit as a key driver of brain-wide functional reorganization during seizures.

## Key findings

- Optogenetic stimulation of piriform cortex Vglut1+ neurons induces generalized seizures in mice.
- The PC-Lent-DG circuit is critical for seizure propagation and brain-wide hyperactivation.
- Disrupting this circuit suppresses seizures and reduces functional connectivity changes.

## Abstract

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.

Seizures originating from the piriform cortex can lead to widespread alterations in brain function, but the circuits responsible for these effects are not well understood. This study in mice shows that the piriform-entorhino-dentate pathway is a key mediator of brain-wide functional reorganization, providing insights on potential therapeutic targets.