Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Area of Science:

• Neuroscience
• Genetics
• Cardiology

Background:

• Sudden unexplained death in epilepsy (SUDEP) is often linked to cardiorespiratory failure.
• Leaky gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene are implicated in SUDEP and sudden cardiac death, causing lethal arrhythmias without structural heart abnormalities.

Purpose of the Study:

• To investigate the impact of a specific human leaky RyR2 mutation (R176Q) on neuronal function and cardiorespiratory control.
• To determine the role of brainstem spreading depolarization (SD) in RyR2 mutation-associated mortality.

Main Methods:

• Utilized a mouse model with the R176Q RyR2 mutation (RQ/+).
• Performed in vivo monitoring for seizures, cardiorespiratory events, and sudden death.
• Conducted in vitro electrophysiological studies on neocortical and brainstem microcircuits to assess synaptic function and SD susceptibility.

Main Results:

• The RQ mutation altered neurotransmitter release probability and lowered the threshold for dorsal medulla spreading depolarization (SD).
• RQ/+ mice exhibited spontaneous seizures, bradycardia, and sudden death; provoked seizures led to apnea, brainstem SD, and cardiorespiratory collapse.
• In vitro studies showed the RQ mutation selectively strengthened excitatory synapses and facilitated SD in both neocortex and brainstem autonomic circuits.

Conclusions:

• Defects in neuronal intracellular calcium homeostasis due to leaky RyR2 mutations can sensitize central autonomic pathways to hypoxic stress.
• Brainstem spreading depolarization (SD) is identified as a critical, previously unrecognized mechanism contributing to premature death in individuals with leaky RYR2 mutations.
• This study links RyR2 gene mutations to SUDEP through impaired brainstem autonomic regulation and SD.