The effects of prenatal stress on the preoptic nuclei of febrile seizure rat models.

Abstract

Febrile seizures are a neurological abnormality that occurs after an underlying systemic infection, leading to fever and followed by convulsions due to neuronal hyper-excitability. Although regarded as benign, prenatal stress, prominent in third world countries, has been shown to exacerbated febrile seizures in offspring by dysregulating the hypothalamus-pituitary-adrenal axis, subsequently leading to increased production of prostaglandin E2 (PGE2) in the preoptic nuclei region of the hypothalamus. Current animal models used to mimic febrile seizures include but are not limited to, lipopolysaccharide (LPS) and kainic acid (KA) administration, or exposure to a hyperthermic environment. However, these models often result in 50% seizure onset with high mortality rates. Therefore, the aims of this study were to refine the models and assess the effects of prenatal stress. Materials and Methods Pregnant Sprague Dawley dams were exposed to restraint stress in their third trimester, and febrile seizures induced in the subsequent pups on postnatal day 14 by one of 2 models i.e. 1. Inducing febrile seizure using the LPS and KA method and 2. via exposure to a hyperthermic environment. Seizures were scored 0 to 5 on a Racine scale. Hypothalamic tissue was harvested and assessed for PGE2 and its receptor (EP3R) concentrations by means of ELISA and PCR respectively. Results Our findings show that modifying the dose to 50 μg/kg LPS and 0.44 mg/kg KA significantly decreased mortality, and thus proved to be most effective. We were also able to induce convulsions through the hyperthermic model. Additionally, we showed that exposure to prenatal stress significantly exacerbated fever and seizure severity, and increased EP3R concentrations. Conclusion and Relevance The modified LPS-KA and heat models both proved sufficient in inducing convulsions, with drastically reduced mortality rates for both stressed and non-stress rat offspring. Albeit it was slightly less severe than previously reported, these simple benign seizures more accurately mimic simple febrile seizures most often experienced by otherwise healthy infants and young children. The hyperthermic model, although sufficient in inducing seizures and maintaining survival, was unable to mimic fever though the appropriate PGE2 release, and thus the modified LPS-KA model was selected as the most effective and most efficient model to use in order to study febrile seizures.