Seizure predisposition after perinatal hypoxia: Effects of subsequent age and of an epilepsy predisposing gene mutation

Authors

  • A. Soren Leonard,

    1. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A
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  • S. Nabeel Hyder,

    1. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A
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  • Brad J. Kolls,

    1. Division of Neurology, Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A
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  • Eric Arehart,

    1. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A
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  • Kim C. W. Ng,

    1. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A
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  • Aravindhan Veerapandiyan,

    1. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A
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  • Mohamad A. Mikati

    Corresponding author
    1. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A
    2. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A
    • Address correspondence to Mohamad A. Mikati, Division of Pediatric Neurology, T0913 Children's Health Center, Duke University Medical Center, Box 3936, 2301 Erwin Road, Durham, NC 27710, U.S.A. E-mail: mohamad.mikati@duke.edu

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Summary

Purpose

There is a gap in our knowledge of the factors that modulate the predisposition to seizures following perinatal hypoxia. Herein, we investigate in a mouse model the effects of two distinct factors: developmental stage after the occurrence of the perinatal insult, and the presence of a seizure predisposing mutation.

Methods

Effects of age: P6 (postnatal day 6) mouse pups were subjected to acute hypoxia down to 4% O2 over the course of 45 min. Seizure susceptibilities to flurothyl-induced seizures (single exposures) and to flurothyl kindling were determined at specific subsequent ages. Effects of mutation: Heterozygote mice, with deletion of one copy of the Kcn1a gene, subjected to P6 hypoxia were compared as adults to wild-type mice with respect to susceptibility to a single exposure to flurothyl and to the occurrence of spontaneous seizures as detected by hippocampal electroencephalography (EEG) and video recordings.

Key Findings

Effects of age: As compared to controls, wild-type mice exposed to P6 hypoxia had a shortened seizure latency in response to a single flurothyl exposure at P50, but not at P7 or P28 (p < 0.04). In addition, perinatal hypoxia at P6 enhanced the rate of development of flurothyl kindling performed at P28–38 (p < 0.03), but not at P7–17. Effects of mutation: Kcn1a heterozygous mice subjected to P6 hypoxia exhibited increased susceptibility to flurothyl-induced seizures at P50 as compared to Normoxia heterozygote littermates, and to wild-type Hypoxia and Normoxia mice. In addition, heterozygotes exposed to P6 hypoxia were the only group in which spontaneous seizures were detected during the period of long-term monitoring (p < 0.027 in all comparisons).

Significance

Our data establish a mouse model of mild perinatal hypoxia in which we document the following: (1) the emergence, after a latent period, of increased susceptibility to flurothyl-induced seizures, and to flurothyl induced kindling; and (2) an additive effect of a gene mutation to the seizure predisposing consequences of perinatal hypoxia, thereby demonstrating that a modifier (or susceptibility) gene can exacerbate the long-term consequences of hypoxic injury.

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