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The Journal of Neuroscience, March 1, 2003, 23(5):1840

Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

Volodymyr I. Dzhala and Kevin J. Staley

Department of Neurology and Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262

In the developing rat hippocampus, ictal epileptiform activity can be elicited easily in vitro during the first three postnatal weeks. Changes in neuronal ion transport during this time cause the effects of GABA_A receptor (GABA_A-R) activation to shift gradually from strongly depolarizing to hyperpolarizing. It is not known whether the depolarizing effects of GABA and the propensity for ictal activity are causally linked. A key question is whether the GABA-mediated depolarization is excitatory, which we defined operationally as being sufficient to trigger action potentials. We assessed the effect of endogenous GABA on ictal activity and neuronal firing rate in hippocampal slices from postnatal day 1 (P1) to P30. In extracellular recordings, there was a strong correlation between the postnatal age at which GABA_A-R antagonists decreased action potential frequency (P23) and the age at which ictal activity could be induced by elevated potassium (P23). In addition, there was a strong correlation between the fraction of slices in which ictal activity was induced by elevated potassium concentrations and the fractional decrease in action potential firing when GABA_A-Rs were blocked in the presence of ionotropic glutamate receptor antagonists. Finally, ictal activity induced by elevated potassium was blocked by the GABA_A-R antagonists bicuculline and SR-95531 (gabazine) and increased in frequency and duration by GABA_A-R agonists isoguvacine and muscimol. Thus, the propensity of the developing hippocampus for ictal activity is highly correlated with the effect of GABA on action potential probability and reversed by GABA_A antagonists, indicating that GABA-mediated excitation is causally linked to ictal activity in this developmental window.

Key words: GABA; action potential; epileptiform activity; hippocampus; CA3; development

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2351840-07$05.00/0

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