AbstractBackgroundProlonged febrile seizures (FS) have both acute and long‐lasting effects on the developing brain. Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children.MethodsThe innate immune activator lipopolysaccharide (LPS) was administered to postnatal day 14 rat (200 μg/kg) and mouse (100 μg/kg) pups 2–2.5 h prior to hyperthermic seizures (HT) induced by hair dryer or heat lamp. To determine whether simulation of infection enhances neuronal excitability, latency to seizure onset, threshold temperature and total number of seizures were quantified. Behavioral seizures were correlated with electroencephalographic changes in rat pups. Seizure‐induced proinflammatory cytokine production was assessed in blood samples at various time points after HT. Seizure‐induced microglia activation in the hippocampus was quantified using Cx3cr1GFP/+ mice.ResultsLipopolysaccharide priming increased susceptibility of rats and mice to hyperthemic seizures and enhanced seizure‐induced proinflammatory cytokine production and microglial activation.ConclusionsPeripheral inflammation appears to work synergistically with hyperthermia to potentiate seizures and to exacerbate seizure‐induced immune responses. By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS.