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

Eric R Wengert,Pravin K Wagley,Ronald P Gaykema,Jung-Bum Shin,Manoj K Patel,Elizabeth L Wagner,Ian C Wenker

doi:10.3389/fnins.2021.581048

Eric R Wengert, Pravin K Wagley + Show 5 more

Open Access

https://doi.org/10.3389/fnins.2021.581048

Copy DOI

Abstract

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.

Highlights

Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden, unexpected, nontraumatic, and non-drowning death of a person with epilepsy for which postmortem examination does not reveal an anatomical or pathological cause of death (Nashef et al, 2012)
2 of 8 D/+ mice were sensitive to audiogenic seizures at P15 (Figure 1B), which we attribute to the fact that mice at this age are likely still developing their auditory system
All 13 D/+ mice tested at P20-21 experienced audiogenic seizures, 11 of which succumbed to sudden death immediately following the seizure (Figure 1C and Supplementary Video 2)

Summary

Introduction

Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden, unexpected, nontraumatic, and non-drowning death of a person with epilepsy for which postmortem examination does not reveal an anatomical or pathological cause of death (Nashef et al, 2012). Such models include the DBA/1&2, Cacna1aS218L, Scn1aR1407X, RyR2R176Q, Scn1a KO, and Kcna KO mouse models as well as inducible kainic acid and maximal electroshock seizure models These approaches have fueled various hypotheses concerning the mechanisms of SUDEP, including brainstem spreading depolarization (Aiba and Noebels, 2015; Aiba et al, 2016; Jansen et al, 2019; Loonen et al, 2019), autonomic dysregulation and cardiac arrhythmias (Glasscock et al, 2010; Auerbach et al, 2013; Kalume et al, 2013), and respiratory arrest due to central (Faingold et al, 2010; Buchanan et al, 2014; Kim et al, 2018; Kruse et al, 2019), or obstructive apnea (Nakase et al, 2016; Villiere et al, 2017; Irizarry et al, 2020). The genetic etiologies of DBA/1&2, Cacna1aS218L, RyR2R176Q, Lmx1bf /f /p, and Kcna KO mice are either unknown, identified from non-epilepsy patient populations, or are manipulations that lead to loss of an entire cell population, receptor subtypes, or ion channels, which are not known to occur in epilepsy patients

Methods

Results

Conclusion