By combining lipopolysaccharide (LPS), a Toll-like Receptor 4 (TLR4) ligand and activator of the innate immune response, with hyperthermia-induced seizures in P14 rat and mouse pups, we demonstrate that simulation of peripheral infection by injection of LPS prior to hyperthermia enhances neuronal excitability, seizure-induced proinflammatory cytokine production, and microglial activation. The gene discussed is TLR4; the disease is infection.