Respiratory dysfunction progresses with age in <i>Kcna1</i>‐null mice, a model of sudden unexpected death in epilepsy

Simeone, Kristina A.; Hallgren, Jodi; Bockman, Charles S.; Aggarwal, Ankita; Kansal, Vikash; Netzel, Lauren; Iyer, Shruthi H.; Matthews, Stephanie A.; Deodhar, Malavika; Oldenburg, Peter J.; Abel, Peter W.; Simeone, Timothy A.

doi:10.1111/epi.13971

Cited by 50 publications

(77 citation statements)

References 41 publications

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“…Methacholine (MCh) induces seizures in KO mice . Following PBS baseline recording, mice were exposed to aerosolized MCh at 6, 12, 24, and 48 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…Following PBS baseline recording, mice were exposed to aerosolized MCh at 6, 12, 24, and 48 mg/mL. Each consecutive MCh concentration was administered for 1 minute and responses were recorded continuously for the subsequent 3 minutes as we have described previously . Seizure monitoring occurred during the entire course of the MCh experiments (4 minutes at PBS and each MCh concentration = 40 minutes).…”

Section: Methodsmentioning

confidence: 99%

“…We have reported previously that elevated breathing frequency and apnea are apparent in KO mice and worsen thru SD 90 (when 90% of mice have died) . Here, we tested three hypotheses.…”

Section: Introductionmentioning

confidence: 91%

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Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

et al. 2020

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Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

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“…Methacholine (MCh) induces seizures in KO mice . Following PBS baseline recording, mice were exposed to aerosolized MCh at 6, 12, 24, and 48 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

et al. 2020

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“…Following a noninvasive challenge with methacholine (ie, a routine test that is used for the diagnosis of asthma in humans), Kcna1 −/− mice exhibited respiratory dysfunction and seizures. This finding might at least partially explain a potential cause of sudden death during epileptic attacks . Despite some similarities of symptoms between episodic ataxia type I and epilepsy, mutations of human KCNA1 and mouse Kcna1 appear to cause somewhat different phenotypes.…”

Section: Role Of Kv Channels In Developmental and Hereditary Disordersmentioning

confidence: 96%

“…The molecular mechanisms that are responsible for megencephaly in mutant mice remain unknown . Different Kcna1 null mouse mutants are characterized by spontaneous, progressive seizures and serve as an animal model of sudden unexpected death in epilepsy (SUDEP).…”

Section: Role Of Kv Channels In Developmental and Hereditary Disordersmentioning

confidence: 99%

Kv2.1 voltage‐gated potassium channels in developmental perspective

Jędrychowska

Korzh

2019

Developmental Dynamics

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Kv2.1 voltage‐gated potassium channels consist of two types of α‐subunits: (a) electrically‐active Kcnb1 α‐subunits and (b) silent or modulatory α‐subunits plus β‐subunits that, similar to silent α‐subunits, also regulate electrically‐active subunits. Voltage‐gated potassium channels were traditionally viewed, mainly by electrophysiologists, as regulators of the electrical activity of the plasma membrane in excitable cells, a role that is performed by transmembrane protein domains of α‐subunits that form the electric pore. Genetic studies revealed a role for this region of α‐subunits of voltage‐gated potassium channels in human neurodevelopmental disorders, such as epileptic encephalopathy. The N‐ and C‐terminal domains of α‐subunits interact to form the cytoplasmic subunit of heterotetrameric potassium channels that regulate electric pores. Subsequent animal studies revealed the developmental functions of Kcnb1‐containing voltage‐gated potassium channels and illustrated their role during brain development and reproduction. These functions of potassium channels are discussed in this review in the context of regulatory interactions between electrically‐active and regulatory subunits.

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A companion to the preclinical common data elements for genomics, transcriptomics, and epigenomics data in rodent epilepsy models. A report of the TASK3‐WG4 omics working group of the ILAE/AES joint translational TASK force

et al. 2022

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The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. The aim of the CDEs is to improve the standardization of experimental designs across a range of epilepsy research‐related methods. Here, we have generated CDE tables with key parameters and case report forms (CRFs) containing the essential contents of the study protocols for genomics, transcriptomics, and epigenomics in rodent models of epilepsy, with a specific focus on adult rats and mice. We discuss the important elements that need to be considered for genomics, transcriptomics, and epigenomics methodologies, providing a rationale for the parameters that should be collected. This is the first in a two‐part series of omics papers with the second installment to cover proteomics, lipidomics, and metabolomics in adult rodents.

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Respiratory dysfunction progresses with age in Kcna1‐null mice, a model of sudden unexpected death in epilepsy

Abstract: The Kcna1 model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.

Cited by 50 publications

References 41 publications

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Kv2.1 voltage‐gated potassium channels in developmental perspective

A companion to the preclinical common data elements for genomics, transcriptomics, and epigenomics data in rodent epilepsy models. A report of the TASK3‐WG4 omics working group of the ILAE/AES joint translational TASK force

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