Authors :
Presenting Author: Benjamin Kreitlow, MS – University of Iowa
Ana Novella Maciel, NONE – Visiting Scholar, Licenciatura en Neurociencias, Falcultad de Medicina, Universidad Nacional Autónoma de México; Ariana Hernandez-Vasquez, NONE – Rotating Student, Secondary Scientist Training Program, Neurology, University of Iowa; Gordon Buchanan, MD PhD – Principle Investigator, Neurology, University of Iowa
Rationale: Persons with epilepsy are at a risk of dying due to sudden unexpected death in epilepsy, or SUDEP. Dravet Syndrome is an epileptic encephalopathy that manifests early in life and is associated with frequent seizures and a high rate of SUDEP. SUDEP events in patients are more common during the nighttime, which is often attributed to seizures occurring during sleep. Multiple mouse models, including the
Scn1aR1407X/+ mouse model of Dravet Syndrome, also have an increased tendency of seizure-related mortality during the nighttime when housed in a 12:12 light-dark cycle, despite being more active during the dark phase of the 24-hour day. Our lab has shown that this nocturnal tendency persists in constant darkness following induced seizures in other models, suggesting that a conserved circadian rhythm may mediate nighttime risk of death. However, the circadian rhythmicity of seizure-associated death has not yet been demonstrated in a genetic mouse model of epilepsy.
Methods: Young (PND 18 – 21)
Scn1aR1407X/+ (knock-in loss-of-function mutation of voltage-gated sodium channel Na
V1.1) mice were used for this study.
Scn1aR1407X/+ mice experience spontaneous seizures early in life and have a high rate of seizure-associated mortality. Mice were reared in a 12:12 light-dark cycle until weaning and then separated into individual cages outfitted with pyroelectric infrared motion sensors for long-term locomotor activity monitoring. Mice were immediately placed into a constant darkness environment to determine free-running period, which was used to identify the endogenous circadian time of day when fatal seizures occurred. Mice were monitored in this manner until experiencing a fatal seizure or until PND 90.
Results: Our lab has previously shown that C57BL/6J mice housed in constant darkness are more likely to die during the subjective night following induced maximal electroshock seizures. Like these prior findings,
Scn1aR1407X/+ mice are more likely to die following spontaneous seizures during the subjective night (22/34 deaths during the subjective night).
Conclusions: Our lab has demonstrated that both induced and spontaneous models of seizure-associated death are time-of-day-dependent and persist in constant darkness, suggesting that an endogenous circadian rhythm may mediate the nighttime susceptibility of seizure-associated death. However, the mechanisms that mediate this risk are unknown. Understanding how the suprachiasmatic nucleus, the central circadian pacemaker, and time-of-day oscillations in neurotransmitters influence the nighttime risk of seizure-associated death may help us better understand the pathophysiological mechanisms underlying SUDEP and may lead to the development of novel chronotherapeutics to reduce SUDEP.
Funding: < NIH/NIGMS T32 GM007337 (University of Iowa MSTP; BLK), Post-Comprehensive Exam Fellowship from University of Iowa Graduate College (BLK), CURE Epilepsy, The Joanna Sophia Grant (GFB), NIH/NINDS R01 NS129722 (GFB), and the Beth L. Tross Epilepsy Professorship (GFB).