Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models
Year: 2015
Type: article
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.
Source: Science Translational Medicine
Authors: Isamu Aiba, Jeffrey L. Noebels
Institution: Baylor College of Medicine
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1183817913, G232043449, G2927260330, The Administrative Core of the Center of SUDEP Research, G3837803025, Autonomic and Imaging Biomarkers of SUDEP, G4713221484, SUDEP Research Alliance: Cardiac Gene and Circuit Mechanisms; Application 7 of 7, Excitability and Plasticity of Developing Epileptic Brain, G960738672
OpenAlex ID: W2163553089