Abstract

The perirhinal cortex (PRh) has extensive interconnections with limbic structures, including the fasciola cinerea (FC), a recently identified node and therapeutic target in temporal lobe epilepsy. However, the neural circuit basis between PRh and FC in seizure progression remains unclear. Here we show that the PRh provides the principal excitatory input to the FC and plays an important role in seizure modulation in male mouse epilepsy models. PRh–FC projections are strongly activated during seizures, and their inhibition delays seizure progression. Moreover, PRh excitatory neurons bidirectionally regulate seizure development and engage multiple distinct downstream pathways, including projections to the FC, infralimbic cortex, and lateral entorhinal cortex. Notably, suppressing PRh activity produces more effective seizure attenuation than targeting individual projections. These findings identify the PRh as a critical hub that coordinates distributed circuits to control seizure progression, highlighting its potential as a therapeutic target for epilepsy treatment. In this study, the authors find that the perirhinal cortex controls hippocampal seizures in male mice via multiple downstream circuits that arise from distinct neuronal subpopulations, including projections to the fasciola cinerea, highlighting it as a promising therapeutic target.