title: Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death.
abstract: Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Isamu
authors.initials: I
authors.lastname: Aiba
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX 77030; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 jnoebels@bcm.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004569:Electroencephalography; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D002118:Calcium
keywords: CPVT; SUDEP; catecholaminergic polymorphic ventricular tachycardia; ryanodine receptor; sudden unexpected death in epilepsy