Grant: Project Grant

Febrile seizures are the most common seizure disorder to affect children who are at a high risk of developing intractable epilepsy. The mechanisms of febrile seizures are unknown which has limited the development of prophylactic treatments. There is strong evidence supporting that febrile seizures occur when children have fever-induced increases in breathing associated with an infection that leads to respiratory alkalosis and subsequent decreased seizure thresholds. Indeed, shifts in acid-base balance are well recognized to alter brain function such that alkalosis leads to hyperexcitability and decreased seizure thresholds, and acidosis producing the opposite effect. Given this link between fever, respiration and febrile seizures, it is important to determine the precise mechanisms by which fever leads to increases in breathing and subsequent respiratory alkalosis. Transient receptor potential vanilloid type 1 receptors (TRPV1) are heat sensitive receptors that play an important role in thermoregulation and responses to inflammation. Importantly, TRPV1 has been localized in the vagus nerve which is a key driver of the fever-induced increases in breathing linked to respiratory alkalosis. The overall goal of this proposal is to test, in an inflammation-based model of febrile seizures established in my laboratory, the link between TRPV1, inflammation and fever-induced increases in breathing accounting for respiratory alkalosis and consequent increased risk of febrile seizures. The results of this study will provide a molecular target upon which, currently unavailable, prophylactic treatments for febrile seizures can be developed and made available for use in clinical practice.