Abstracts

Rationale: The underlying pathophysiology in the majority of pediatric epilepsies is still incompletely understood. To improve this understanding new models are needed that mimic the reality that most cases of pediatric epilepsy are non-lesional and unlikely to be from a single gene abnormality. Herein we describe the behavioral and anatomical features of a new model of seizure susceptibility. Methods: Groups of three pregnant Sprague Dawley female rats were transported either during early (EG), or middle (MG), gestation and subsequently assigned to one of three groups: na ve, control (saline i.p.) or experimental (LPS; 100 g/kg i.p.). Injections were performed on the 15th day of gestation (G15). Pregnancy and parturition then proceeded undisturbed and pups remained with their mothers. Pups were then challenged with a febrile convulsions (FC) paradigm on the 14th post natal day (P14) involving an injection of 200 g/kg of LPS followed 2.5 hours later by 1.75 mg/kg of kainic acid and videotaped for 3 hours for behavioral scoring. Twenty-four hours after seizure provocation animals were euthanized and their brains processed for immunohistochemical reactivity (IR) and analysis of FosB, c-fos, c-jun, protein expression as well as Fluoro-jade C expression using standard procedures. Results: The paradigm did not adversely affect parturition nor alter the typical litter size or sex ratio. Maternal transport during later gestation however resulted in increased pup seizure severity and more lethal events (p<0.001). Both prenatal saline and LPS at G15 decreased pup seizure severity in a graduated manner: an effect that was seen at both transport times (p<0.05 to p<0.001). Qualitative and quantitative immunohistochemical analysis revealed significant differences in FosB-IR expression in the hippocampal subregions, amygdala, piriform, entorhinal and retrosplenial cortices, nucleus accumbens, periventricular regions of both the thalamus and hypothalamus, the substantia nigra and the locus coeruleus (p<0.05 to p<0.001). Similar patterns were observed in the IR expression of c-fos and c-jun with slight variations. This differential expression did not appear to be a result of cell death as there was minimal expression of Fluoro-jade C. Conclusions: These results suggest that maternal prenatal stress and immune challenge modify newborn seizure susceptibility and that the magnitude and direction of the effect was dependent on the timing of the stressor(s). Further, the combination of the FC-induced behavioral manifestations and neuronal activation pattern in the P14 pups suggests a change in the circuit activation that was related to the maternal prenatal stress. Ongoing studies are examining both the underlying pathophysiological mechanisms of the model, as well as the impact of the prenatal stressors on neurodevelopment and epileptogenesis.