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

Publication ,  Journal Article
Leonard, AS; Hyder, SN; Kolls, BJ; Arehart, E; Ng, KCW; Veerapandiyan, A; Mikati, MA
Published in: Epilepsia
October 2013

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.

Duke Scholars

Published In

Epilepsia

DOI

EISSN

1528-1167

Publication Date

October 2013

Volume

54

Issue

10

Start / End Page

1789 / 1800

Location

United States

Related Subject Headings

  • Seizures
  • Neurology & Neurosurgery
  • Mutation
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Mice
  • Kv1.1 Potassium Channel
  • Kindling, Neurologic
  • Hypoxia
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Leonard, A. S., Hyder, S. N., Kolls, B. J., Arehart, E., Ng, K. C. W., Veerapandiyan, A., & Mikati, M. A. (2013). Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation. Epilepsia, 54(10), 1789–1800. https://doi.org/10.1111/epi.12347
Leonard, A Soren, S Nabeel Hyder, Brad J. Kolls, Eric Arehart, Kim C. W. Ng, Aravindhan Veerapandiyan, and Mohamad A. Mikati. “Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation.Epilepsia 54, no. 10 (October 2013): 1789–1800. https://doi.org/10.1111/epi.12347.
Leonard AS, Hyder SN, Kolls BJ, Arehart E, Ng KCW, Veerapandiyan A, et al. Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation. Epilepsia. 2013 Oct;54(10):1789–800.
Leonard, A. Soren, et al. “Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation.Epilepsia, vol. 54, no. 10, Oct. 2013, pp. 1789–800. Pubmed, doi:10.1111/epi.12347.
Leonard AS, Hyder SN, Kolls BJ, Arehart E, Ng KCW, Veerapandiyan A, Mikati MA. Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation. Epilepsia. 2013 Oct;54(10):1789–1800.
Journal cover image

Published In

Epilepsia

DOI

EISSN

1528-1167

Publication Date

October 2013

Volume

54

Issue

10

Start / End Page

1789 / 1800

Location

United States

Related Subject Headings

  • Seizures
  • Neurology & Neurosurgery
  • Mutation
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Mice
  • Kv1.1 Potassium Channel
  • Kindling, Neurologic
  • Hypoxia
  • Humans