Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

Wenker, Ian C.; Blizzard, Elizabeth A.; Wagley, Pravin K.; Patel, Manoj K.

doi:10.3389/fnins.2021.795145

Cited by 6 publications

(9 citation statements)

References 62 publications

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“…For example, rhombomere-specific Cre mice have been produced that can target different regions of the mid-and hindbrain (Sun et al, 2017). Indeed, when excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) receptors were expressed under control of Cre in these mice, CNO administration produced apnea and death, similar to what seizure-induced death in our mouse models (Wengert et al, 2021b;Wenker et al, 2021Wenker et al, , 2022.…”

Section: The Neural Circuitry Of Tonic Phase Apneamentioning

confidence: 68%

“…Comparison of spontaneous, audiogenic, and hippocampal stimulated seizures in D/+ mice Spontaneous (Figure 1A), HC electrically stimulated (Figure 1B), and audiogenic (Figure 1C) seizures of D/+ mice all have very similar semiology (Supplementary Video 1), including brief wild running prior to a pronounced tonic phase coincident with apnea (Wengert et al, 2021b;Wenker et al, 2021Wenker et al, , 2022. One difference stands out: all recorded spontaneous and HC stimulated seizures produced cortical ictal activity that preceded the tonic phase; however, cortical ictal activity was delayed until after initiation of the tonic phase of audiogenic seizures (Figures 1C,D), suggesting that cortical ictal activity is not necessary for production of the tonic phase or apnea.…”

Section: Resultsmentioning

confidence: 98%

“…In the D/+ mice, spontaneous seizures are quite similar in semiology to both audiogenic (Wengert et al, 2021b) and HC stimulated seizures (Wenker et al, 2022). These seizures are of the tonic variety: a brief wild running phase is followed by a prolonged tonic phase, with occasional clonic activity prior to Model depicting neural circuitry involved in tonic phase apnea.…”

Section: The Tonic Phase and Seizure-induced Apneamentioning

confidence: 93%

“…Custom electrocorticogram (ECoG)/electrocardiogram (ECG) headsets (P1 Technologies, Roanoke, VA, United States) were implanted in 6–8-week-old mice using standard aseptic surgical techniques as done previously ( Wengert et al, 2021a , b ; Wenker et al, 2021 , 2022 ). Anesthesia was induced with 5% and maintained with 0.5–3% isoflurane.…”

Section: Methodsmentioning

confidence: 99%

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Forebrain epileptiform activity is not required for seizure-induced apnea in a mouse model of Scn8a epilepsy

Wenker

Boscia

Lewis

et al. 2022

Front. Neural Circuits

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Sudden unexpected death in epilepsy (SUDEP) accounts for the deaths of 8–17% of patients with epilepsy. Although the mechanisms of SUDEP are essentially unknown, one proposed mechanism is respiratory arrest initiated by a convulsive seizure. In mice, we have previously observed that extended apnea occurs during the tonic phase of seizures. Although often survived, tonic seizures became fatal when breathing did not immediately recover postictally. We also found that respiratory muscles were tonically contracted during the apnea, suggesting that muscle contraction could be the cause of apnea. In the present study, we tested the hypothesis that pyramidal neurons of the motor cortex drive motor units during the tonic phase, which produces apnea. Mice harboring the patient-derived N1768D point mutation of an Scn8a allele were crossed with transgenic mice such that inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) receptors were selectively expressed in excitatory forebrain neurons. We then triggered audiogenic and hippocampal (HC) stimulated seizures under control conditions and when excitatory forebrain neurons were inhibited with the synthetic ligand Clozapine-N-Oxide (CNO). We found that inhibition with CNO was sufficient to increase seizure threshold of HC stimulated, but not audiogenic, seizures. In addition, regardless of seizure type, CNO nearly eliminated epileptiform activity that occurred proximal to the tonic phase; however, the seizure behaviors, notably the tonic phase and concomitant apnea, were unchanged. We interpret these results to indicate that while cortical neurons are likely critical for epileptogenesis and seizure initiation, the behavioral manifestations of tonic seizures are generated by neural circuitry in the mid- and/or hindbrain.

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Section: The Neural Circuitry Of Tonic Phase Apneamentioning

confidence: 68%

Section: Resultsmentioning

confidence: 98%

Section: The Tonic Phase and Seizure-induced Apneamentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Forebrain epileptiform activity is not required for seizure-induced apnea in a mouse model of Scn8a epilepsy

Wenker

Boscia

Lewis

et al. 2022

Front. Neural Circuits

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“…SUDEP is a leading cause of death in DS [Shmuley 2016], but the mechanism(s) by which this sudden death occurs is not understood. We evaluated respiratory function and lung morphology in a mouse model of DS to determine whether breathing abnormalities in this model were consistent with other Dravet mouse models [Kuo, et al 2019; Kim, et al 2018; Wenker, et al 2022] and with clinical SUDEP data [Ryvlin, et al 2013; Kim, et al 2018; Villella, et al 2018]. Specifically, breathing patterns were compared between heterozygous Scn1a A1783V/WT (Het) DS mice and WT littermate mice during basal and post-ictal periods.…”

Section: Discussionmentioning

confidence: 94%

Breathing dysfunction and alveolar damage in a mouse model of Dravet syndrome

Goh

Deering-Rice

Nguyen

et al. 2022

Preprint

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SUMMARYObjectiveThe incidence of Sudden Unexpected Death in Epilepsy (SUDEP) is especially high in those with Dravet syndrome (DS). Risk factors have been identified, but the mechanism(s) by which death occurs is not fully understood. Evidence supports ventilatory dysfunction in the pathophysiology of SUDEP. Understanding specific respiratory patterns present at baseline and after seizures at different ages, as well as the health of lung tissue, will allow us to better understand how sudden death occurs in this population.MethodsWhole body plethysmography (WBP) was used to monitor respiration before and after electrically induced seizure in the Scn1aA1783V/WT mouse model of DS weekly for a period of four weeks. Following the four-week WBP study, lungs from surviving animals were collected and stained with hematoxylin and eosin and Weigert’s elastin and the density of tissue and elastin were analyzed.ResultsBreathing was diminished in the DS mouse at baseline and following evoked seizures in younger aged mice (P18-P24), consistent with prolonged post-ictal inspiratory time and low respiratory drive compared to the response seen in older animals. In older DS mice, consisting of those that have survived a critical period for mortality, the response to seizure was more robust and included higher respiratory drive, peak inspiratory and expiratory flow rates, tidal and expiratory volumes, and breathing frequency compared to wild-type and relative to baseline. Alveolar damage was also observed in P46-P52 DS mice.SignificanceDifferences in specific respiratory parameters in younger DS animals, during the time when mortality is greatest, compared to older DS animals (i.e. those that have survived the critical period) may allow us to better understand respiratory differences contributing to SUDEP. Lung tissue damage in DS may also contribute to respiratory dysfunction in SUDEP.KEY POINTSBaseline respiration is diminished in DS mice compared to wild type.Electrically induced seizure produced a different respiratory response in younger DS mouse compared to older DS animals.Alveolar septal damage is present in DS mice.Baseline and post-ictal breathing dysfunction and inefficient oxygenation and CO2 clearance likely potentiated by lung damage may serve as a potential mechanism by which SUDEP occurs in DS.

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Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

Smith,

Richerson,

Kouchi

et al. 2023

Epilepsia

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Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of Sudden Unexpected Death in Epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting the limitations of these models and the intrinsic difficulties of investigating SUDEP. The interpretation of pre‐clinical data and their translation to diagnostic and therapeutic developments in patients thus require a high level of confidence in their relevance to model the human situation.Preclinical models of SUDEP models are heterogeneous and range from rodent and non‐rodent species. A critical aspect is whether the animals have isolated seizures exclusively induced by a specific trigger, such models where seizures are elicited by electrical stimulation or pharmacological intervention or DBA mouse strains, or whether they suffer from epilepsy with spontaneous seizures, with or without spontaneous SUDEP, either of non‐genetic epilepsy etiology or of genetically‐based developmental and epileptic encephalopathies. All these models have advantages and potential disadvantages, but it is important to be aware of these limitations to interpret data appropriately in a translational perspective. The majority of models with spontaneous seizures are of a genetic basis whereas SUDEP cases with a genetic basis represent only a small proportion of the total number. In almost all models, cardio‐respiratory arrest occurs during the course of the seizure, contrary to that in patients observed at the time of death, potentially raising the issue of whether we are studying models of SUDEP or models of peri‐seizure death. However, some of these limitations are impossible to avoid and can in part be dependent on specific features of SUDEP, which may be difficult to model. Several preclinical tools are available to address certain gaps in SUDEP pathophysiology, which can be used to further validate current preclinical models.

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Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

Cited by 6 publications

References 62 publications

Forebrain epileptiform activity is not required for seizure-induced apnea in a mouse model of Scn8a epilepsy

Forebrain epileptiform activity is not required for seizure-induced apnea in a mouse model of Scn8a epilepsy

Breathing dysfunction and alveolar damage in a mouse model of Dravet syndrome

Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

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