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.sudden unexpected death in epilepsy | SUDEP | catecholaminergic polymorphic ventricular tachycardia | CPVT | ryanodine receptor U p to 10% of individuals with seizures of unknown cause and without known structural cardiac pathology die of sudden unexpected death in epilepsy (SUDEP), and this morbidity is second only to stroke in the number of life-years lost (1). Despite the high mortality rate, comparable to that of sudden infant death syndrome (SIDS), the exact causes are unclear, and there is no effective prediction or intervention. Cardiorespiratory dysfunction and collapse have been observed following generalized tonicclonic seizures in a small number of monitored cases (2), "near SUDEP" cases (3), and mouse SUDEP models (4-6). Genes linked with the most common cardiac LQT syndromes including LQT1 (KCNQ1), LQT2 (KCNH2/HERG), and LQT3 (SCN5A) are expressed in both the human heart and brain, where mutations in the kinetics of these membrane ion channels prolong depolarization and produce combined seizure, cardiac arrhythmia, and sudden death phenotypes (7,8). Because mutations in these ion channel genes currently explain only a small fraction of SUDEP cases (7), the search for additional genes and mechanisms is a high priority to understand and treat sudden death risk.Along with cardiac arrhythmia, recent findings in voltage-gated ion channelopathy models point to an extracardiac, central autonomic involvement of these genes in the events leading to sudden cardiac death. Spreading depolarization (SD) is a slow propagating wave of cellular depolarization that occurs in human brain and is known to contribute to transient neurological deficits during migraine ...

Ryanodine receptor 2 (RYR2) mutation: A potentially novel neurocardiac calcium channelopathy manifesting as primary generalised epilepsy

“…2c) have demonstrated spontaneous EEG-positive generalised seizures independent of cardiac arrhythmia [3]. Furthermore, other RYR2 mutant mice have demonstrated spreading depolarisation across the neocortex and brainstem dorsal medulla autonomic microcircuits [8]. Recent whole exome sequencing analyses have identified RYR2 as a candidate gene in genetic generalised epilepsy and early infantile epileptic encephalopathy [9].…”

“…One possible reason for the rarity of seizure occurrence in this well-established cardiac arrhythmogenic disorder is enhancement of membrane after-hyperpolarisation in excitatory neurons which acts as a "brake" for aberrant cortical discharges. 8 Furthermore, ion channel gene mutations responsible for cardiac channelopathies such as hereditary long QT syndromes (i.e. KCNQ1, KCNH2 and SCN5A) have been reported in patients with a neurogenic seizure phenotype and SUDEP; these ion channels have demonstrated co-expression in the heart and in the brain [11].…”

“…carbamazepine, phenytoin and lacosamide should probably be avoided in RYR2 mutation-positive patients with epilepsy, as they are known to trigger cardiac arrhythmias [12]. Furthermore, such patients should receive specialised counselling with regard to risk of SUDEP [8,11] and importance of maximising seizure freedom with avoidance of seizure triggers and adherence to AEDs.…”

Double-Nanodomain Coupling of Calcium Channels, Ryanodine Receptors, and BK Channels Controls the Generation of Burst Firing

“…Importantly, because this mechanism requires convergence of multiple cellular components, pathological changes in any one component could bias neurons to a ‘ryanodine-like’ condition of elevated firing. Indeed, recent studies indicate roles of altered function of neuronal ryanodine receptor type 1 and 2 (RyR1, RyR2) in some models of seizure susceptibility (Aiba et al, 2016; Mikami et al, 2016). …”

Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats

“…Systemic KA produces sympathoactivation with pressor response, tachycardia, and lengthening of QT interval; [3][4][5] it also reduces tidal volume and rhythmicity, and in some animals ultimately leads to sudden death due to laryngospasm. 6,7 Two further hypotheses proposed to explain seizure-related apneas and fatal cardiorespiratory collapse are the following: (1) spreading depolarization (similar to spreading depression) propagating from the forebrain into the brainstem, demonstrated in several mouse models [8][9][10] ; and (2) laryngospasm triggered by gastric acid reflux (gastric acid reflux has been shown following systemic KA). 11 Although autonomic consequences of systemic KA have been attributed to the effects of seizure activity, 5 and sympathetic and parasympathetic brainstem are activated during seizure activity, 4 a contribution from KA acting directly on the brainstem cannot be excluded.…”