Nagham Eldroubi
Research Mentor(s): Joanna Mattis
Mentor Department:
Authors:
Session: Session 2 (10:00am – 10:50am)
Presentation Type: Poster 3
Abstract
Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by treatment-resistant epilepsy, including seizures triggered by fevers, developmental delay, and high rates of Sudden Unexpected Death in Epilepsy (SUDEP). DS is primarily caused by pathogenic variants in the SCN1A gene, which encodes the alpha subunit of the Nav1.1 voltage-gated sodium channel. This study examines the effects of early-life hyperthermia-induced seizures on subsequent SUDEP rates in the well-characterized Scn1a+/- mouse model of DS. We used hyperthermia to evoke seizures in Scn1a+/- mice, monitoring seizure threshold and SUDEP rates. Survival curve comparisons found that Scn1a+/- mice subjected to repeated seizures had significantly higher mortality rates than non-heated Scn1a+/- mice, not recapitulated in WT mice that were equivalently heated but that did not have seizures. Given anecdotal reports of heterogeneity in phenotypic severity across different Cre lines, we compared Scn1a+/- mice with the F1 progeny from triple-transgenic (Scn1a+/-; Chat-Cre;td) mice: triple-transgenic Scn1a+/-; Chat-Cre;tdT mice had significantly higher mortality rates than Scn1a+/- mice in both conditions. Overall, our results show that early-life seizures worsen the phenotype of Scn1a+/- mice. The significant differences in short-term SUDEP rates will enable studies to uncover SUDEP mechanisms: as serotonergic dysfunction is hypothesized to be a risk factor for SUDEP, we have initiated stereological quantification of serotonergic neurons in the Dorsal Raphe Nucleus (DRN) to determine whether Scn1a+/- heated mice (i.e., mice at high risk of SUDEP) have reduced cell counts.
