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

Abstract

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.

Cell Type-Specific Synaptic Dynamics of Synchronized Bursting in the Juvenile CA3 Rat Hippocampus

“…These results indicate that blockade of fast inhibition promotes multiple effects leading to a change of burst strength and frequency. Slices displaying ictal activity (Dzhala and Staley, 2003) or in which gabazine application triggered cyclic electrographic seizures (Khazipov et al, 2004) without recovering to an interictal-like bursting rhythm were discarded from this analysis.…”

Disrupted Dentate Granule Cell Chloride Regulation Enhances Synaptic Excitability during Development of Temporal Lobe Epilepsy

“…Depolarized E GABA increases granule cell excitability by altering synaptic integration One important consequence of depolarizing GABA currents is the potential for GABA induced action potentials (Dzhala and Staley, 2003;Gulledge and Stuart, 2003). E GABA in all post-STEP cells was not sufficiently depolarizing to reach action potential threshold during an IPSP (from a V m of Ϫ65 mV).…”

“…This endows the dentate gyrus with the properties of a tightly regulated filter, limiting throughput between the entorhinal cortex and the hippocampus (Collins et al, 1983;Heinemann et al, 1992;Lothman et al, 1992). Although this is true in the dentate gyrus of adult animals, in immature dentate granule cells, E GABA is more depolarized (Ben-Ari et al, 1989;Owens et al, 1996;Hollrigel et al, 1998;Dzhala and Staley, 2003). Shifts in E GABA during postnatal maturation are mediated by increased expression of the neuron specific K ϩ Cl Ϫ cotransporter, KCC2, which extrudes Cl Ϫ , setting a more hyperpolarized Cl Ϫ equilibrium (Payne et al, 1996;Rivera et al, 1999;Lee et al, 2005).…”

Epilepsy: A Review of Selected Clinical Syndromes and Advances in Basic Science

“…It was speculated that these depolarizing GABAergic responses endowed those pyramidal neurons with properties that favored epileptic firing (Cohen et al, 2002). The explanation for the depolarizing GABA responses was presumed to be similar to the developmentally regulated GABA excitatory phenomenon seen early in ontogeny, that is, an abnormal chloride gradient causing the chloride reversal potential to reside at a depolarized level relative to resting potential (Ben-Ari, 2002;Cohen et al, 2003;Dzhala and Staley, 2003). It is unknown whether this phenomenon is widespread, whether it is mediated by specific GABA receptor subtypes, and whether it is due to neuronal injury.…”