Audiogenic seizure as a model of sudden death in epilepsy: A comparative study between four inbred mouse strains from early life to adulthood

Martin, Benoı̂t; Dieuset, Gabriel; Pawluski, Jodi L.; Costet, Nathalie; Biraben, Arnaud

doi:10.1111/epi.16432

Cited by 25 publications

(31 citation statements)

References 21 publications

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“…Furthermore, young DBA/1 mice tend to be small (Martin et al . 2020). It was doubtful that 23–30‐day‐old DBA/1 mice would be able to reliably operate running a running wheel.…”

Section: Methodsmentioning

confidence: 99%

The effect of time‐of‐day and circadian phase on vulnerability to seizure‐induced death in two mouse models

Purnell

Petrucci

et al. 2021

The Journal of Physiology

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Key points Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in patients with refractory epilepsy. SUDEP typically occurs during the night, although the reason for this is unclear. We found that, in normally entrained mice, time‐of‐day alters vulnerability to seizure‐induced death. We found that, in free‐running mice, circadian phase alters the vulnerability to seizure‐induced death. These findings suggest that circadian rhythmicity may be responsible for the increased night‐time prevalence of SUDEP Abstract Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy‐related death. SUDEP typically occurs during the night following a seizure. Many aspects of mammalian physiology are regulated by circadian rhythms in ways that might make seizures occuring during the night more dangerous. Using two mouse models of seizure‐induced death, we demonstrate that time‐of‐day and circadian rhythms alter vulnerability to seizure‐induced death. We exposed normally entrained DBA/1 mice to a potentially seizure‐inducing acoustic stimulus at different times of day and compared the characteristics and outcomes of the seizures. Time‐of‐day did not alter the probability of a seizure but it did alter the probability of seizure‐induced death. To determine whether circadian rhythms alter vulnerability to seizure‐induced death, we induced maximal electroshock seizures in free‐running C57BL/6J mice at different circadian time points at the same time as measuring breathing via whole body plethysmography. Circadian phase did not affect seizure severity but it did alter postictal respiratory outcomes and the probability of seizure‐induced death. By contrast to our expectations, in entrained and free‐running mice, vulnerability to seizure‐induced death was greatest during the night and subjective night, respectively. These findings suggest that circadian rhythmicity may be responsible for the increased night‐time prevalence of SUDEP and that the underlying mechanism is phase conserved between nocturnal and diurnal mammals. All of the seizures in the present study were induced during wakefulness, indicating that the effect of time point on vulnerability to seizure‐induced death was not the result of sleep. Understanding why SUDEP occurs more frequently during the night may inform future preventative countermeasures.

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“…Furthermore, young DBA/1 mice tend to be small (Martin et al . 2020). It was doubtful that 23–30‐day‐old DBA/1 mice would be able to reliably operate running a running wheel.…”

Section: Methodsmentioning

confidence: 99%

The effect of time‐of‐day and circadian phase on vulnerability to seizure‐induced death in two mouse models

Purnell

Petrucci

et al. 2021

The Journal of Physiology

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“…This discrepancy could be attributed to the fact that for most audiogenic seizureinduce death experiments, respiratory activity is assessed by visualization, which could make it difficult to ascertain breathing, or the lack thereof, during convulsions. Another factor could be that tonic seizures in DBA1/2J mice, which are used in the majority of preclinical SUDEP research, almost always produce death, making S-IRA and death coincident with one another (Martin et al, 2020). Considering tonic seizures are associated with apnea in humans (Gastaut et al, 1963;Wyllie, 2015), it is likely that most, if not all, tonic seizures in mouse models produce apnea.…”

Section: Tonic Phase Apnea and Failure Of Breathing Recoverymentioning

confidence: 99%

“…It is unclear whether tonic phase apnea is necessary for postictal apnea and death, as there is no method to selectively prevent the tonic phase from occurring. However, it has been shown that DBA1/2J and 129/SvTer mice die from tonic, but not clonic, seizures (Martin et al, 2020), implying the tonic phase is important and perhaps necessary for seizure-induced death. Thus, determining cellular and molecular underpinnings of both tonic phase apnea and failure of breathing recovery will be important foci for future SUDEP research.…”

Section: Tonic Phase Apnea and Failure Of Breathing Recoverymentioning

confidence: 99%

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

et al. 2021

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death amongst patients whose seizures are not adequately controlled by current therapies. Patients with SCN8A encephalopathy have an elevated risk for SUDEP. While transgenic mouse models have provided insight into the molecular mechanisms of SCN8A encephalopathy etiology, our understanding of seizure-induced death has been hampered by the inability to reliably trigger both seizures and seizure-induced death in these mice. Here, we demonstrate that mice harboring an Scn8a allele with the patient-derived mutation N1768D (D/+) are susceptible to audiogenic seizures and seizure-induced death. In adult D/+ mice, audiogenic seizures are non-fatal and have nearly identical behavioral, electrographical, and cardiorespiratory characteristics as spontaneous seizures. In contrast, at postnatal days 20–21, D/+ mice exhibit the same seizure behavior, but have a significantly higher incidence of seizure-induced death following an audiogenic seizure. Seizure-induced death was prevented by either stimulating breathing via mechanical ventilation or by acute activation of adrenergic receptors. Conversely, in adult D/+ mice inhibition of adrenergic receptors converted normally non-fatal audiogenic seizures into fatal seizures. Taken together, our studies show that in our novel audiogenic seizure-induced death model adrenergic receptor activation is necessary and sufficient for recovery of breathing and prevention of seizure-induced death.

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“…To test for audiogenic seizures mice were taken from their home cage and transferred to a clean test cage where they were allowed to acclimate for ~20 seconds before the onset of the acoustic stimulus. Similar to a method described previously (Martin et al, 2020), a sonicator (Branson 200 ultrasonic cleaner) was used to produce the audiogenic stimulus directly adjacent to the test cage. The stimulus duration lasted for 50 seconds or until the animal had a behavioral seizure.…”

Section: Audiogenic Seizure Testmentioning

confidence: 99%

Somatostatin-positive Interneurons Contribute to Seizures inSCN8AEpileptic Encephalopathy

Wengert

Wedgwood

Wagley

et al. 2021

Preprint

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SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. We found that selective expression of the R1872W mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of wild-type SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A encephalopathy, but epilepsy in general.

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Audiogenic seizure as a model of sudden death in epilepsy: A comparative study between four inbred mouse strains from early life to adulthood

Cited by 25 publications

References 21 publications

The effect of time‐of‐day and circadian phase on vulnerability to seizure‐induced death in two mouse models

The effect of time‐of‐day and circadian phase on vulnerability to seizure‐induced death in two mouse models

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

Somatostatin-positive Interneurons Contribute to Seizures inSCN8AEpileptic Encephalopathy

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