Seizures are common during the neonatal period, often due to
hypoxic-ischemic encephalopathy and may contribute to
acute brain injury and the subsequent development of cognitive deficits and childhood
epilepsy. Here we explored short- and long-term consequences of neonatal
hypoxia-induced
seizures in 7 day old C57BL/6J mice. Seizure activity, molecular markers of
hypoxia and histological injury were investigated acutely after
hypoxia and response to chemoconvulsants and animal behaviour was explored at adulthood.
Hypoxia was induced by exposing pups to 5%
oxygen for 15 min (global
hypoxia). Electrographically defined
seizures with behavioral correlates occurred in 95% of these animals and
seizures persisted for many minutes after restitution of normoxia. There was minimal morbidity or mortality. Pre- or post-
hypoxia injection of
phenobarbital (50mg/kg) had limited efficacy at suppressing
seizures. The hippocampus from neonatal
hypoxia-seizure mice displayed increased expression of
vascular endothelial growth factor and the immediate early gene c-fos, minimal histological evidence of cell injury and activation of
caspase-3 in scattered neurons. Behavioral analysis of mice five weeks after
hypoxia-induced
seizures detected novel anxiety-related and other behaviors, while performance in a spatial memory test was similar to controls. Seizure threshold tests with
kainic acid at six weeks revealed that mice previously subject to neonatal
hypoxia-induced
seizures developed earlier, more frequent and longer-duration
seizures. This study defines a set of electro-clinical, molecular, pharmacological and behavioral consequences of
hypoxia-induced
seizures that indicate short- and long-term deleterious outcomes and may be a useful model to investigate the pathophysiology and treatment of neonatal
seizures in humans.