Perinatal hypoxia is the single most common cause of seizures in the neonatal period. A subset of infants with seizures due to hypoxic encephalopathy develop chronic epilepsy. Several major questions regarding the pathophysiology of hypoxia-induced neonatal seizures remain unanswered. First, it is not clear why the immature brain is so susceptible to the epileptogenic effects of hypoxia, because seizures much less commonly complicate hypoxia/ischemia in the adult. Second, seizures complicating hypoxic encephalopathy con be refractory to anticonvulsant therapy that is effective in adult seizure disorders, indicating that the mechanism underlying perinatal hypoxia-induced seizures may be age-dependent. Third, it is not known how the acute perinatal seizures relate to later epilepsy, and whether the two phenomena share a common mechanism. The investigators have developed a unique model of perinatal hypoxia in the rat which exhibits both acute and chronic epileptogenic effects of hypoxia. Hypoxia induces seizure only during a critical developmental window of 10-12 days of age in the rat, and these animals have lowered seizure susceptibility as adults. Hippocampal slices removed acutely after hypoxia or in adulthood show enhanced excitability. Their recent studies indicate that hypoxia downregulates gene and protein expression for the GluR2 AMPA subunit and also results in a decreased in cells stained with the GABA synthetic enzyme, GAD. Here they propose to characterized the cellular and molecular effects of perinatal hypoxia in the hippocampus with respect to these new findings.
Specific Aims : 1) To identify alterations in synaptic currents which underlie the acute and chronic epileptogenic effects of perinatal hypoxia. 2) To characterize changes in gene and protein expression of AMPA and NMDA subunits following perinatal hypoxia. 3) To evaluate the developmental distribution of AMPA subunit mRNAs and proteins in non hypoxic rats at different age intervals before, during and after the window of vulnerability for the epileptogenic effect of hypoxia. 4) To determine whether the observed decreased in interneurons stained with GAD-67 in adult CA1 after perinatal hypoxia is due to selective cell death or to a downregulation of GAD activity in surviving cells. Using this multidisciplinary approach, we aim to characterize the cellular and molecular effects of perinatal hypoxia in the hippocampus and to begin to assess the impact of pharmacological therapies on these effects. The long term goal of this proposal is to define age-specific therapeutic strategies for the treatment of epileptogenesis in the developing brain.
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