title: Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, U.S.A.
authors.forename: A Soren
authors.initials: AS
authors.lastname: Leonard
authors.forename: S Nabeel
authors.initials: SN
authors.lastname: Hyder
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Kolls
authors.forename: Eric
authors.initials: E
authors.lastname: Arehart
authors.forename: Kim C W
authors.initials: KC
authors.lastname: Ng
authors.forename: Aravindhan
authors.initials: A
authors.lastname: Veerapandiyan
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Mikati
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D005481:Flurothyl / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D051662:Kv1.1 Potassium Channel / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology
chemical_list: C496947:Kcna1 protein, mouse; D051662:Kv1.1 Potassium Channel; D005481:Flurothyl
keywords: Acute hypoxia; Developing brain; Kcn1a; Kindling; Mouse