Epileptogenic effect of hypoxia in the immature rodent brain

Abstract

The response to cerebral hypoxia/ischemia may be different in the neonate compared to other age groups. An in vivo model was developed in the rat to determine whether there are age-dependent differences in the effects of hypoxia on electroencephalographic (EEG) activity. EEG recordings were obtained from Long Evans hooded rats deprived of oxygen at five ages: postnatal days 5 to 7, 10 to 12, 15 to 17, 25 to 27, and 50 to 60. Oxygen concentration was varied from 0, 2, 3, and 4% between animals. EEGs were recorded in all animals before, during, and at 1 hour after exposure to the hypoxic condition and at 1 to 7 days afterward in a subset of animals. All animals were deprived of oxygen until the onset of apnea and bradycardia to 20 to 40% of baseline heart rate values. Hypoxia resulted in isoelectric EEG significantly more frequently in the animals deprived of oxygen at postnatal days 25 to 27 and 50 to 60 than in the younger age groups. A highly significant effect was that the animals deprived at postnatal days 5 to 17 revealed a high incidence of epileptiform EEG activity during hypoxia. In contrast, the older animals exhibited only rare isolated EEG spikes before reaching an isoelectric EEG. The severity of hypoxia-induced epileptiform EEG changes was highest in the animals subjected to moderately hypoxic conditions (3% and 4% oxygen) at postnatal days 10 to 12. Furthermore, epileptiform changes persisted for hours to days following prolonged episodes of hypoxia in the younger animals. This study demonstrates a unique response of the immature brain to exhibit epileptiform activity during hypoxia.

Neonatal Seizures

“…CNS maturation is determined by gestational age: a premature infant will exhibit neurologic reflex, electroencephalographic, 11 and dendritic maturation patterns comparable with those of a term infant only when that infant's conceptual age approaches 40 weeks. [12][13][14][15] Accordingly, the ability of an infant who has sustained neurologic insult to manifest seizures may vary with gestational age. Furthermore, the reliance on clinical observation to identify seizures would have excluded neonates who had electrographic seizures without clinical manifestations.…”

AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain

“…Rat pups were maintained in a 12 h light/dark cycle facility. To induce hypoxic seizures, we followed our previously published methods (Jensen et al, 1991(Jensen et al, , 1992. Briefly, rat pups at ages P10 -P11 were exposed to global hypoxia (reducing O 2 to 4 -7% by infusion of N 2 gas into the chamber) for 15 min, and the number of myoclonic jerks and tonic clonic seizures were counted during the period of hypoxia.…”

“…CaN is a Ca 2ϩ -calmodulin-dependent phosphatase, and therefore can potentially be activated by numerous sources of activitydependent Ca 2ϩ entry into neurons. In the P10 rat, in which susceptibility to the epileptogenic effects of hypoxia is highest (Jensen et al, 1991;Jensen, 1997), hippocampal and cortical pyramidal neurons express Ca 2ϩ -permeable AMPARs because of a maturation-dependent lower expression of the GluR2 subunit in the first 2 weeks of life Kumar et al, 2002). Because this route of Ca 2ϩ entry exists only in the very immature brain, we investigated whether seizure-induced activation of Ca 2ϩ -permeable AMPARs played a pivotal role in this CaNmediated signaling pathway.…”

“…To investigate age-specific mechanisms of epileptogenesis in the neonatal brain, we used a rodent model that mimics the acute seizures and chronic proepileptogenic effects of neonatal hypoxia observed clinically. In this model, global hypoxia induces seizures in rat pups at postnatal day 10 (P10) to P12 but not in younger or older rat pups (Jensen et al, 1991(Jensen et al, , 1992. Furthermore, after hypoxia-induced neonatal seizures, rats exhibit long-term increases in seizure susceptibility (Jensen et al, 1991(Jensen et al, , 1992 as well as early and long-lasting increases in hippocampal and cortical network excitability (Jensen et al, 1998).…”

“…In this model, global hypoxia induces seizures in rat pups at postnatal day 10 (P10) to P12 but not in younger or older rat pups (Jensen et al, 1991(Jensen et al, , 1992. Furthermore, after hypoxia-induced neonatal seizures, rats exhibit long-term increases in seizure susceptibility (Jensen et al, 1991(Jensen et al, , 1992 as well as early and long-lasting increases in hippocampal and cortical network excitability (Jensen et al, 1998). In immature rats, hypoxia-induced seizures and chronic hyperexcitability can be blocked by treatment with antagonists to AMPA receptors (AMPARs) but not NMDA receptors (NMDARs) (Jensen et al, 1995;Koh and Jensen, 2001;Koh et al, 2004).…”