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

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 : P 6 (postnatal day 6) mouse pups were subjected to acute hypoxia down to 4% O 2 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 K cn1a gene, subjected to P 6 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 P 6 hypoxia had a shortened seizure latency in response to a single flurothyl exposure at P 50, but not at P 7 or P 28 (p < 0.04). In addition, perinatal hypoxia at P 6 enhanced the rate of development of flurothyl kindling performed at P 28–38 (p < 0.03), but not at P 7–17 . Effects of mutation : K cn1a heterozygous mice subjected to P 6 hypoxia exhibited increased susceptibility to flurothyl‐induced seizures at P 50 as compared to N ormoxia heterozygote littermates, and to wild‐type H ypoxia and N ormoxia mice. In addition, heterozygotes exposed to P 6 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.