ACUTE AND CHRONIC INCREASES IN EXCITABILITY IN RAT HIPPOCAMPAL SLICESAFTER PERINATAL HYPOXIA IN-VIVO

We have previously shown that hypoxia induces both acute and chronic e pileptogenic effects that are age dependent. Global hypoxia (3-4% O-2) induces seizure activity in the developing brain [postnatal day (P)10 -12] but not at younger or older ages. Adult rats with prior seizures induced by hypoxia at P10 show increased seizure susceptibility to che mical convulsants compared with controls. In the present study, we tes ted the hypothesis that acute and chronic epileptogenic effects of hyp oxia are demonstrable in hippocampus both in vivo and in vitro. Depth electrode recordings confirmed the presence of ictal activity within h ippocampus in P10 rats during global hypoxia. Hippocampal slices prepa red from P10 pups killed at 10 min after recovery from hypoxia showed evidence of increased excitability. Extracellular field recordings rev ealed that the amplitude and duration of long-term potentiation (LTP) was increased significantly in area CA1 of hippocampal slices removed from hypoxic pups. In addition, extracellular recordings within areas CA1 and CA3 showed significantly longer afterdischarge durations in re sponse to kindling stimuli in slices from hypoxic pups compared with c ontrols. To evaluate whether there were also long-term changes in hipp ocampal excitability, hippocampal slices were prepared from adult rats that had underwent hypoxia at P10 and compared with slices from adult litter-mate controls. A Mg2+-free medium was superfused to induce epi leptiform activity within the slices. Extracellular recordings from st ratum pyramidale of area CA1 showed that Mg2+-free media induced signi ficantly more frequent ictal discharges in slices from previously hypo xic rats compared with controls. These results provide evidence that t he naturally occurring stimulus of hypoxia can result in both acute an d chronic changes in the excitability of the CA1 neuronal network. The se results parallel our previous in vivo studies demonstrating that gl obal hypoxia acutely increases excitability in the immature brain and that hypoxia during the age window similar to P10 results in long-last ing increases in seizure susceptibility within hippocampus. Our result s suggest that the age-dependent epileptogenic effects of hypoxia are in part mediated by a direct and permanent effect on neuronal excitabi lity within hippocampal neuronal networks.