Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models

Aiba, Isamu; Noebels, Jeffrey L.

doi:10.1126/scitranslmed.aaa4050

Cited by 276 publications

(280 citation statements)

References 41 publications

(66 reference statements)

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“…Once triggered, the profound local depolarization of neurons and glia compromises electrical brain activity and energy metabolism. We recently reported that cortical seizures lead to ictal hypoxia and SD in mouse SUDEP models, resulting in cortical electroencephalography (EEG) depression and terminal cardiorespiratory arrest (11). We also found that slices of dorsal medulla from these Kv1.1-and Nav1.1-deficient SUDEP mice facilitated SD generation in vitro following hypoxic challenge.…”

mentioning

confidence: 85%

“…Propagation rate was calculated only for the first SD to avoid contamination by the run-down effect from repetitive tissue depolarization (57). Cortical EEG, EKG, brainstem DC, and respiratory signals were recorded as described previously (11). After recovery from surgery, mice showed heart rates >550 bpm and respiration rates between 1 and 2 Hz.…”

Section: Methodsmentioning

confidence: 99%

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

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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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 ...

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mentioning

confidence: 85%

Section: Methodsmentioning

confidence: 99%

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

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The relationship among BSD (24), PGES (25), and peri-ictal apnea remains unclear. It is not known whether BSD occurs in our model.…”

Section: Monitoring Of Patients With Ds With Video Eeg Telemetrymentioning

confidence: 99%

“…A variety of mechanisms have been proposed for SUDEP (1,2,(4)(5)(6), including cardiac arrhythmias (7)(8)(9)(10), dysfunction of autonomic control (11)(12)(13)(14)(15), apnea/hypoventilation (3,(16)(17)(18)(19)(20)(21), airway obstruction (22), pulmonary edema (23), brain stem spreading depolarization (BSD) (24), and postictal generalized EEG suppression (PGES) (25). Many investigators have focused on cardiac tachyarrhythmias as the cause of death, in part because of an association between SUDEP and mutations of genes expressed in the heart, such as those that underlie long QT syndrome (10,(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

Kim¹,

Bravo²,

Thirnbeck³

et al. 2018

Journal of Clinical Investigation

117

168

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“…Seizures can spread centrally to activate midbrain arousal areas or medullary neurons that control vagus nerve functions (4, 7) and activity-dependent plasticity in central vagal neurons occurs in a variety of diseases (8,9). Because seizures can alter responsiveness of brainstem neurons that integrate cardiorespiratory functions, it seems reasonable to speculate that seizure-related neuroplasticity in the brainstem might eventually develop in epilepsy to influence both cardiac and respiratory functions (7). Changes in how the brainstem regulates cardiorespiratory functions may be compounded by intrinsic cardiac arrhythmias that develop due to cardiomyocyte expression of neuronal Na + channels.…”

Section: Seizures Epilepsy and Sudep: A Change Of Heart?mentioning

confidence: 99%

Seizures, Epilepsy, and SUDEP: A Change of Heart?

Smith¹

2016

Epilepsy Curr

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CommentarySudden unexpected death in epilepsy (SUDEP) is defined by the sudden, unexplainable death of an individual with epilepsy and accounts for approximately 17% of epilepsy-related deaths. Patients with longstanding epilepsy characterized by frequent generalized tonic-clonic seizures that are relatively poorly controlled appear to be at highest risk. Physiological factors that may contribute to SUDEP include peri-ictal, centrally-originating autonomic irregularities leading to cardiac and respiratory arrest. Electrocardiographic abnormalities characterized mainly by rhythm and repolarization changes, including prolonged QT interval, are also associated with the occurrence of generalized seizures in patients with epilepsy and may contribute to SUDEP, especially when it occurs postictally (1). Similar to clinical reports, arrhythmias associated with altered cardiac Na + channel function have been demonstrated in rodent epilepsy models, including the kainate-induced status epilepticus model of temporal lobe epilepsy (TLE) (2), but the mechanisms supporting these changes were previously undescribed. Biet and colleagues investigated epilepsy-related changes in several Na + currents that underlie action potential repolarization and timing in cardiomyocytes as they relate to cardiac conduction and excitability. Significant functional and molecular cardiac channel remodeling was detected in conjunction with development of spontaneous seizures in the TLE model, consistent with epilepsy-induced overexpression of a neuronal Na + channel isoform in cardiomyocytes, which predispose to an increase in QT interval.Normally, cardiomyocyte action potential generation and inactivation are tightly regulated in order to maintain appropriate cardiac contraction rhythms. As in central neurons, cardiac action potentials are mediated by Na + currents, although neuronal and cardiomyocyte Na + currents differ in their kinetics and are composed of different channel isoforms. Cardiac Na + currents are mediated mainly by a relatively tetrodotoxin (TTX)-insensitive Na + channel isoform, Na V 1.5, encoded by the SCNA5 gene, which imparts relatively fast activation and inactivation kinetics. Normally, Na + currents and action potentials in neurons are mediated by a TTX-sensitive Na + channel isoform, Na V 1.1, which has somewhat slower kinetics and is encoded by the SCNA1 gene. Using electrophysiological recordings in vitro, the authors found that action potential duration was increased in cardiomyocytes from epileptic rats, and TTX was more potent in reducing action potential duration and peak Na + current amplitude in epileptic rats than in controls. Activation threshold was also hyperpolarized relative to controls. Interestingly, these changes were very similar to Na + current increases reported in hippocampal neurons from spontaneously epileptic rats (3). Increased activation of a late Na + (Na L ) current tends to increase cardiac action potential duration, which can result physiologically in increased QT interval that can lead to lon...

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Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models

Cited by 276 publications

References 41 publications

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

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

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

Seizures, Epilepsy, and SUDEP: A Change of Heart?

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