Abstracts

RATIONALE: The immature brain is prone to seizures but the underlying mechanisms are poorly understood. We explored the hypothesis that increased susceptibility of the developing brain to seizures is due to the excitatory action of GABA on the immature neurons.
METHODS: Extracellular and patch-clamp recordings from CA3 pyramidal cells were performed on 500 mm thick hippocampal slices from Sprague Dawley rats.
RESULTS: Under control conditions, slices from the postnatal days P0-13 rats displayed spontaneous epileptiform activity in the form of spontaneous population bursts (SPBs) that coincided with Giant Depolarising Potentials on the cellular level. Exposure of slices to high-potassium (7.5- 8.5 mM) solution induced various epileptiform patterns at various ages: during the first postnatal week, an increase in the frequency of SPBs; during the second postnatal week, multiple population spikes or tonic-clonic discharges; and starting from the third postnatal week onwards only SPBs-like events. Epileptiform events were scored and Gauss fit of age-dependence of the high-potassium induced epileptiform activity revealed a peak of epileptogenesis at P10[plusminus]2. In the second experiment, we determined the time course of the developmental change in the effect of GABA(A) receptor activation on the pyramidal cells using non-invasive extracellular recordings from CA3 pyramidal cells. Activation of GABA(A) receptors by the selective agonist isoguvacine induced an increase in the frequency of extracellular spikes during the first two postnatal weeks and inhibition later on in development. Boltzman fit of the age-dependence of the GABA(A) effect on neuronal activity revealed that the developmental switch from excitation to inhibition occurs at P14[plusminus]1.
CONCLUSIONS: Thus, the critical period of highest epileptogenesis in the developing rat hippocampus coincides with the late phase of the excitatory action of GABA and it is terminated by the transition of GABA from excitatory to inhibitory. We therefore suggest that excitatory action of GABA via GABA(A) receptors is an important factor contributing to epileptogenesis during the critical period, in addition to other factors such as the development of recurrent collateral synapses between the pyramidal cells. Excitatory action of GABA is also responsible for generation of [dsquote]physiological[dsquote] precocious epilepsy during the two first postnatal weeks in the rat hippocampus that is reminiscent of the immature [dsquote]trace alternant[dsquote] pattern in human EEG.
[Supported by: NINDS (NS27984), Ligue Francaise contre l[ssquote]Epilepsie and the French Medical Research Council]