Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation
Leonard, AS; Hyder, SN; Kolls, BJ; Arehart, E; Ng, KC; Veerapandiyan, A; Mikati, MA
| HERO ID | 5381726 |
|---|---|
| In Press | No |
| Year | 2013 |
| Title | Seizure predisposition after perinatal hypoxia: effects of subsequent age and of an epilepsy predisposing gene mutation |
| Authors | Leonard, AS; Hyder, SN; Kolls, BJ; Arehart, E; Ng, KC; Veerapandiyan, A; Mikati, MA |
| Journal | Epilepsia |
| Volume | 54 |
| Issue | 10 |
| Page Numbers | 1789-1800 |
| Abstract | <strong>PURPOSE: </strong>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.<br /><br /><strong>METHODS: </strong>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.<br /><br /><strong>KEY FINDINGS: </strong>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).<br /><br /><strong>SIGNIFICANCE: </strong>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. |
| Doi | 10.1111/epi.12347 |
| Pmid | 24032507 |
| Wosid | WOS:000325141500012 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |