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

Epilepsia. 2018 Feb;59(2):345-357. doi: 10.1111/epi.13971. Epub 2018 Jan 12.

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.

Keywords: Kv1.1 knockout; apnea; hypopnea; mortality; seizures; survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apnea / complications
  • Apnea / genetics*
  • Apnea / metabolism
  • Bronchoconstrictor Agents / pharmacology
  • Death, Sudden*
  • Disease Models, Animal
  • Disease Progression
  • Epilepsy
  • Epilepsy, Temporal Lobe / complications
  • Epilepsy, Temporal Lobe / physiopathology*
  • Gene Expression
  • Hyperventilation / chemically induced
  • Hypoxia / complications
  • Hypoxia / genetics*
  • Hypoxia / metabolism
  • Kv1.1 Potassium Channel / genetics*
  • Kv1.1 Potassium Channel / metabolism
  • Methacholine Chloride / pharmacology
  • Mice
  • Mice, Knockout
  • Muscle, Smooth / drug effects
  • Respiratory Insufficiency / complications
  • Respiratory Insufficiency / genetics*
  • Respiratory Insufficiency / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tachypnea / complications
  • Tachypnea / genetics
  • Tachypnea / metabolism
  • Tidal Volume
  • Trachea / drug effects

Substances

  • Bronchoconstrictor Agents
  • Kcna1 protein, mouse
  • Methacholine Chloride
  • Kv1.1 Potassium Channel

Associated data

  • GENBANK/ab32433
  • GENBANK/NS072179
  • GENBANK/NS085389