Authors :
Presenting Author: Ana Teresa Novella Maciel, BS – Univeristy of Iowa
Benjamin Kreitlow, MS – Univeristy of Iowa
Gordon Buchanan, MD, PhD – University of Iowa
Rationale:
Epilepsy is a common neurological disease characterized by spontaneous seizures. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with medically refractory epilepsy. Dravet Syndrome is a genetic type of epilepsy that is associated with frequent seizures and a high rate of SUDEP. Seizure-associated death occurs more commonly at night, in both humans and in multiple mouse models, including the Scn1aR1407X/+ mouse model of Dravet Syndrome. Our lab has shown that the nighttime tendency in this model persists in constant darkness following spontaneous seizures, suggesting a conserved circadian rhythm that might mediate nighttime risk of death. However, this has not been demonstrated following heat-induced seizures. Methods:
In this project, mice were reared on a 12:12 light-dark (LD) cycle until weaning, then divided into two groups: one transferred to constant darkness (DD) in individual cages with pyroelectric infrared motion sensors for locomotor activity monitoring (to confirm circadian entrainment), and the other maintained in LD. Mice were assigned to one of six time points (0, 4, 8, 12, 16, or 20 hours) corresponding to Zeitgeber Time (ZT) for LD mice or Circadian Time (CT) for DD mice. These time points were selected to capture two phases each of light and dark periods plus the light/dark transitions—critical intervals our lab has previously identified as high-risk for seizures. After 4–6 days in DD (allowing stabilization of free-running rhythms), heat-induced seizures were performed at designated times by gradually heating mice under a ceramic lamp until severe seizures (defined by full hindlimb extension) occurred. Survival, core body temperature at seizure onset, and additional seizure physiology (e.g., latency, severity) were recorded.
Results:
Consistent with prior findings from our lab, these results demonstrate that Scn1aR1407X/+ mice exhibit significantly higher mortality following heat-induced seizures during the night and subjective night (DD).
Conclusions:
Our work has established that this time-of-day dependency in seizure-associated death persists across both induced and spontaneous seizure models, including in constant darkness—strongly implicating endogenous circadian mechanisms in mediating nighttime susceptibility to fatal seizure outcomes.Funding:
NIH/NINDS R01NS129722 and CURE Epilepsy The Joanna Sophia Grant