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

Abstract

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.

• Authors: A Soren Leonard, S Nabeel Hyder, Brad J Kolls, Eric Arehart, Kim C W Ng, Aravindhan Veerapandiyan, Mohamad A Mikati
• Journal: Epilepsia (Epilepsia) Vol. 54 Issue 10 Pg. 1789-800 (Oct 2013) ISSN: 1528-1167 [Electronic] United States
• PMID: 24032507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Chemical References

• Kcna1 protein, mouse
• Kv1.1 Potassium Channel
• Flurothyl

Topics

• Age Factors
• Animals
• Animals, Newborn (genetics, physiology)
• Disease Models, Animal
• Electroencephalography
• Flurothyl (pharmacology)
• Genetic Predisposition to Disease (genetics)
• Heterozygote
• Hippocampus (physiopathology)
• Humans
• Hypoxia (complications)
• Kindling, Neurologic (drug effects, physiology)
• Kv1.1 Potassium Channel (genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mutation (genetics)
• Seizures (chemically induced, etiology, genetics, physiopathology)