title: Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models.
abstract: Cardiorespiratory collapse after a seizure is the leading cause of sudden unexpected death in epilepsy (SUDEP) in young persons, but why only certain individuals are at risk is unknown. To identify a mechanism for this lethal cardiorespiratory failure, we examined whether genes linked to increased SUDEP risk lower the threshold for spreading depolarization (SD), a self-propagating depolarizing wave that silences neuronal networks. Mice carrying mutations in Kv1.1 potassium channels (-/-) and Scn1a sodium ion channels (+/R1407X) phenocopy many aspects of human SUDEP. In mutant, but not wild-type mice, seizures initiated by topical application of 4-aminopyridine to the cortex led to a slow, negative DC potential shift recorded in the dorsal medulla, a brainstem region that controls cardiorespiratory pacemaking. This irreversible event slowly depolarized cells and inactivated synaptic activity, producing cardiorespiratory arrest. Local initiation of SD in this region by potassium chloride microinjection also elicited electroencephalographic suppression, apnea, bradycardia, and asystole, similar to the events seen in monitored human SUDEP. In vitro study of brainstem slices confirmed that mutant mice had a lower threshold for SD elicited by metabolic substrate depletion and that immature mice were at greater risk than adults. Deletion of the gene encoding tau, which prolongs life in these mutants, also restored the normal SD threshold in Kv1.1-mutant mouse brainstem. Thus, brainstem SD may be a critical threshold event linking seizures and SUDEP.
authors: Developmental Neurogenetics Laboratory, Department of Neurology, and NIH/NINDS Center for SUDEP Research, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Isamu
authors: I
authors: Aiba
authors: Developmental Neurogenetics Laboratory, Department of Neurology, and NIH/NINDS Center for SUDEP Research, Baylor College of Medicine, Houston, TX 77030, USA. Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. jnoebels@bcm.edu.
authors: Jeffrey L
authors: JL
authors: Noebels
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000375:Aging / Q000473:pathology; D000818:Animals; D001933:Brain Stem / Q000503:physiopathology*; D003645:Death, Sudden; D004195:Disease Models, Animal; D004569:Electroencephalography; D006323:Heart Arrest / Q000150:complications / Q000503:physiopathology*; D051662:Kv1.1 Potassium Channel / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D012640:Seizures / Q000150:complications / Q000503:physiopathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins; D051662:Kv1.1 Potassium Channel