摘要:SummaryEpilepsy is a circuit-level brain disorder characterized by hyperexcitatory seizures with unclear mechanisms. Here, we investigated the causal roles of calretinin (CR) neurons in the posterior intralaminar thalamic nucleus (PIL) in hippocampal seizures. Using c-fos mapping and calcium fiber photometry, we found that PIL CR neurons were activated during hippocampal seizures in a kindling model. Optogenetic activation of PIL CR neurons accelerated seizure development, whereas inhibition retarded seizure development. Further, viral-based circuit tracing verified that PIL CR neurons were long-range glutamatergic neurons, projecting toward various downstream regions. Interestingly, selective inhibition of PIL-lateral amygdala CR circuit attenuated seizure progression, whereas inhibition of PIL-zona incerta CR circuit presented an opposite effect. These results indicated that CR neurons in the PIL play separate roles in hippocampal seizures via distinct downstream circuits, which complements the pathogenic mechanisms of epilepsy and provides new insight for the precise medicine of epilepsy.Graphical abstractDisplay OmittedHighlights•PIL CR neurons are activated during hippocampal seizures•Optogenetic control of PIL CR neurons bidirectionally modulates seizure development•LA-projecting and ZI-projecting CR circuits present opposite effects in seizure modulationBiological sciences; Molecular neuroscience; Cellular neuroscience