Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus

Persistent activation of GABA(A) receptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by alpha 5-subunit-containing GABA(A) receptors (alpha 5GABA(A)Rs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that alpha 5GABA(A)Rs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of delta-subunit-containing GABA(A) receptors predominates. In epileptic tissue, alpha 5GABA(A)Rs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of alpha 5GABA(A)Rs by other GABA(A) receptor subtypes. These results reveal multiple components of tonic GABA(A) receptor-mediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures.