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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Objective: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD). Methods: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/−, and Kcna1−/− littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. Results: Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near-SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration(EC50) in isolated Kcna1+/+ and Kcna1−/− trachea. Significance: 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.

Original languageEnglish (US)
Pages (from-to)345-357
Number of pages13
JournalEpilepsia
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2018

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Sudden Death
Methacholine Chloride
Epilepsy
Seizures
Respiratory Insufficiency
Hyperventilation
Apnea
Trachea
Smooth Muscle
Respiration
Tachypnea
Lung
Oximetry
Temporal Lobe Epilepsy
Tidal Volume
Muscle Contraction
Mechanics
Reverse Transcriptase Polymerase Chain Reaction
Proteins
Western Blotting

Keywords

  • Kv1.1 knockout
  • apnea
  • hypopnea
  • mortality
  • seizures
  • survival

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Simeone, K. A., Hallgren, J., Bockman, C. S., Aggarwal, A., Kansal, V., Netzel, L., ... Simeone, T. A. (2018). Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy. Epilepsia, 59(2), 345-357. https://doi.org/10.1111/epi.13971

Respiratory dysfunction progresses with age in Kcna1-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.

In: Epilepsia, Vol. 59, No. 2, 01.02.2018, p. 345-357.

Research output: Contribution to journalArticle

Simeone, KA, Hallgren, J, Bockman, CS, Aggarwal, A, Kansal, V, Netzel, L, Iyer, SH, Matthews, SA, Deodhar, M, Oldenburg, PJ, Abel, PW & Simeone, TA 2018, 'Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy', Epilepsia, vol. 59, no. 2, pp. 345-357. https://doi.org/10.1111/epi.13971
Simeone KA, Hallgren J, Bockman CS, Aggarwal A, Kansal V, Netzel L et al. Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy. Epilepsia. 2018 Feb 1;59(2):345-357. https://doi.org/10.1111/epi.13971
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. / Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy. In: Epilepsia. 2018 ; Vol. 59, No. 2. pp. 345-357.
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abstract = "Objective: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD). Methods: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/−, and Kcna1−/− littermates were assessed during 3 age ranges when up to ~30{\%}, ~55{\%}, and ~90{\%} of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. Results: Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near-SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration(EC50) in isolated Kcna1+/+ and Kcna1−/− trachea. Significance: 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.",
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AU - Simeone, Kristina A.

AU - Hallgren, Jodi

AU - Bockman, Charles S.

AU - Aggarwal, Ankita

AU - Kansal, Vikash

AU - Netzel, Lauren

AU - Iyer, Shruthi H.

AU - Matthews, Stephanie A.

AU - Deodhar, Malavika

AU - Oldenburg, Peter J.

AU - Abel, Peter W.

AU - Simeone, Timothy A.

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N2 - Objective: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD). Methods: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/−, and Kcna1−/− littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. Results: Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near-SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration(EC50) in isolated Kcna1+/+ and Kcna1−/− trachea. Significance: 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.

AB - Objective: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD). Methods: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/−, and Kcna1−/− littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. Results: Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near-SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration(EC50) in isolated Kcna1+/+ and Kcna1−/− trachea. Significance: 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.

KW - Kv1.1 knockout

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KW - hypopnea

KW - mortality

KW - seizures

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