Abstracts

RATIONALE: Hypoxia is the leading cause of neonatal seizures and can lead to long-term epilepsy. We previously reported that perinatal hypoxia-induced seizures in rat result in decreased seizure threshold and increased hippocampal excitability (J Neurophys 1998;79:73). These functional changes are associated with decreased expression of the AMPA receptor (AMPAR) subunit GluR2 and increased permeability of AMPARs to Ca++ in hippocampal pyramidal neurons. We therefore hypothesize that increased AMPAR-mediated Ca++ influx after perinatal hypoxia-induced seizures contributes to aberrant synaptic plasticity and epileptogenesis. To determine if AMPARs can mediate epileptogenesis in this model, we examined responses to "kindling" stimuli in hippocampal slices in the presence of an NMDA receptor antagonist. In this paradigm, repeated tetanic stimuli typically evoke ictal field discharges that increase in an NMDA receptor-dependent manner. METHODS: Seizures were induced by global hypoxia (4-7% O2, 15 min) in rat pups on postnatal day (P) 10, and hippocampal slices were obtained at P14-18 from hypoxia-treated and control animals. CA3 Schaffer collateral axons were electrically stimulated and field potentials recorded from CA1 s. pyramidale. After obtaining I/O curves, the NMDA receptor antagonist APV (100 ?M) was added to the bath. A tetanus (100 Hz, 2 sec) was applied once every 10 minutes at a stimulus intensity twice that which evoked the maximum population spike. The numbers of spikes in each tetanus-induced afterdischarge (AD) were counted for analysis. RESULTS: In the presence of APV, the initial tetani evoked ictal-like ADs in the majority of slices from both the control and hypoxic groups. With repeated tetani, however, increased (kindled) ADs were observed in >70% of slices from the hypoxic group, compared to <20% of control slices. CONCLUSIONS: The results indicate increased capacity for non-NMDA receptor-mediated hippocampal kindling following perinatal hypoxia-induced seizures. This supports the hypothesis that increased AMPAR-mediated Ca++ influx contributes to perinatal hypoxia-induced epileptogenesis.