Abstracts

Rationale: Compelling evidence implicates interleukin cytokine system imbalance in fever-infection related epilepsy syndrome (FIRES) patients. An intrinsic functional deficiency in endogenous IL-1 receptor antagonist (IL-1ra) activity potentially leads to an unopposed pathological inflammatory state, “a spark to the blaze,” driven by over-active IL-1β, a master cytokine of local and systemic inflammation and innate immunity.   Given the compromised IL-1ra function in FIRES patients, we propose to utilize IL-1ra deficient mice as an experimental model of FIRES to mimic this salient feature.  We aimed to determine if IL-1 receptor antagonist (IL-1Ra) deficient mice at postnatal day (P) 15, P20, and P25 exhibit increased susceptibility to seizures by experimentally induced fever.

Methods: Breeding pairs of IL-1Ra (+/-) mice were purchased from Jackson Laboratory. We exposed the F1 to experimental fever (lipopolysaccharide (LPS) + hyperthermia) to compare the seizure susceptibility among three groups: wild type (WT; +/+; n=15), heterozygous (HT; +/-; n=8), and knock-out (KO; -/-; n=5) at three different ages: P15, P20, and P25.  Mice were injected with LPS (100ug/kg i.p.) 2 hours before exposure to a heat lamp to raise core temperature up to 41°C. Rectal temperature was measured every two minutes, and mice were removed and hydrated with subcutaneous saline if the core temperature reached above 40°C. Hyperthermia was terminated after 30 minutes, and all animals were cooled on a metal plate and rehydrated with subcutaneous saline. Behavioral seizures onset and duration during hyperthermia were recorded.  Student’s t-tests (Prism v. 5.0, GraphPad) were used to compare body weights, seizure occurrence, latency to seizure onset, and seizure threshold temperature between groups. Data are expressed as the mean ± standard error of the mean (SEM), and significance was defined as p< 0.05 for all tests.