Interleukin-1beta contributes to the generation of experimental febrile seizures

Abstract

Fever can provoke "febrile" seizures (FS). Because complex FS may promote development of temporal lobe epilepsy, understanding their mechanisms is clinically important. Using an immature rodent model and transgenic technology, we examined the role of interleukin-1beta, (IL-1beta), a pyrogenic, proinflammatory cytokine, in FS. IL-1beta receptor-deficient mice were resistant to experimental FS. This resistance appeared independent of genetic background and was attributed to lack of IL-1beta signaling, because exogenous cytokine reduced seizure threshold in wild-type but not receptor-deficient mice independent of strain. In addition, high IL-1beta doses induced seizures only in IL-1beta receptor-expressing mice. These data indicate that IL-1beta signaling contributes critically to fever-induced hyperexcitability underlying FS, constituting a potential target for their prevention.

Fig 1

(A) Mice deficient in the interleukin-1 receptor (IL-1R1^−/−) are more resistant to the generation of experimental febrile seizures (FSs) compared with wild-type control mice of a similar genetic background (129/Sv). Threshold temperatures for the onset of these seizures, a reliable measure of susceptibility, were significantly greater in IL-1R1^−/− mice: 42.4 ± 0.3°C versus 41.3 ± 0.2°C in wild-type mice. (See Materials and Methods for details of IL-1R1^−/− mice generation and background.) (B) Hippocampal electroencephalogram recordings from unanesthetized wild-type mouse. Normal θ rhythm is evident, which is attenuated by progressive hyperthermia and is replaced by epileptiform discharges. The behavioral correlates of the electroencephalogram seizure consist of sudden immobility associated with reduced response to stimulation (“altered consciousness”), which is typically associated with limbic automatisms. * indicates p < 0.05

Fig 2

The resistance to experimental febrile seizures (FSs) in IL-1R1^−/− mice appears independent of potential confounders related to their genetic background. (A) Experimental FS threshold in (wild-type) C57BL mice is less than in (wild-type) 129/Sv mice (39.7 ± 0.2°C vs 41.3 ± 0.2°C). A difference of gene repertoires between these two strains could underlie changes in susceptibility to the induction of experimental FSs. However, the absence of interleukin-1 type 1 receptor (IL-1R1) leads to significant increase of seizure threshold in both genetic strains. The asterisk indicates different from threshold of wild-type 129/Sv and C57BL. Minus sign indicates different from C57BL. (B) Infusion of 5ng IL-1β, but not of vehicle (water) into the cerebral ventricles (icv), does not affect seizure threshold of the IL-1R1^−/− mice, but significantly (asterisk) decreases seizure threshold of wild-type mice of a similar genetic background, suggesting that the resistance to experimental FSs found in IL-1R1^−/− mice is specific to the null mutation in the receptor gene.

Fig 3

High doses of interleukin (IL)-1β (116ng) result in limbic behavioral and electrical seizures only in wild-type mice. (A, B) Hippocampal electroencephalographic (EEG) recordings from mice before (A) and 3 hours after IL-1β administration (B). (A) Normal EEGs in wild-type (129/Sv) and IL-1R1^−/− mice. (B) Differential effects of IL-1β in these two groups include: prolonged spike trains develop in wild-type 129/Sv mice, whereas the EEG remains normal in IL-1R1^−/− mice. (C) Quantitative analysis of IL-1β–induced spike duration in the 6 hours after administration. IL-1β induces limbic seizures, with a mean duration of 37.0 ± 15.2 minutes (n = 5), in all wild-type mice, whereas no IL-1R1^−/− mice (n = 5) experienced development of seizures.