Farah Abdelhak
Research Mentor: Joanna Mattis
Mentor Department: Neurology, Medicine
Author(s): Farah Abdelhak, Krystal Santiago Colon, Alexander Hollier, Megan Lee, Keiko Arakawa, Xiaogang Zhang, Joanna Mattis
Session: Session 1 (9:00 AM – 9:50 AM)
Presentation Type: Poster 4
Abstract
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of mortality in patients with epilepsy, yet its underlying mechanisms remain poorly understood. Respiratory dysfunction during or following seizures is proposed as a major contributor to SUDEP, potentially arising from seizure-induced impairment of brain regions that regulate breathing and arousal. A history of frequent convulsive seizures is the most significantly identified risk factor for SUDEP, but it is not known whether or how prior seizures change the subsequent peri-ictal behavior of respiratory circuits. This is a crucial question, as therapeutics designed to protect the brain from seizure-evoked changes in respiratory circuits would represent a paradigm shift in epilepsy care. Here, we used a Scn1a+/- mouse model of Dravet syndrome, a severe developmental and epileptic encephalopathy with high SUDEP rates. Prior work in our lab established that repeated hyperthermia-induced seizures in Scn1a+/- mice greatly increase short-term SUDEP risk, such that genotype-matched mice can be stratified into low-risk (LR) and high-risk (HR) SUDEP phenotypes. Using this framework, we examined the medullary raphe nucleus (MRN), a key respiratory brain region, to assess for differential peri-ictal activation in LR versus HR groups. Following seizure induction, brains from HR and LR Scn1a+/- and wild-type (WT) littermate control mice were sectioned, immunostained for cFOS (to label activated neurons) and for Tph2 (to label serotonergic neurons), imaged, and analyzed using condition-blinded manual cell counting in Fiji. Preliminary data suggest that HR Scn1a+/- mice have increased overall MRN neuronal activation, as well as MRN serotonergic neuronal activation, compared to both LR Scn1a+/- and WT groups. Ongoing work will expand analyses to the Kölliker-Fuse nucleus and other respiratory and arousal nuclei. Overall, this work will identify candidate regions that may mediate peri-ictal dysregulation of respiration in subjects with high seizure burden, towards a mechanistic understanding of SUDEP risk.
