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The Journal of Neuroscience, October 26, 2005, 25(43):10016-10024; doi:10.1523/JNEUROSCI.2520-05.2005
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Neurobiology of Disease
Multiple and Plastic Receptors Mediate Tonic GABAA Receptor Currents in the Hippocampus
Annalisa Scimemi,1
Alexey Semyanov,1,2
Günther Sperk,3
Dimitri M. Kullmann,1 and
Matthew C. Walker1
1Institute of Neurology, University College London, London WC1N 3BG, United Kingdom, 2Neuronal Circuit Mechanisms Research Group, The Institute of Physical and Chemical Research (RIKEN) Brain Science Institute, Wako-shi, Saitama 351-0198, Japan, and 3Department of Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria
Persistent activation of GABAA 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  5-subunit-containing GABAA receptors (5GABAARs). 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 5GABAARs 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  -subunit-containing GABAA receptors predominates. In epileptic tissue, 5GABAARs 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 5GABAARs by other GABAA receptor subtypes. These results reveal multiple components of tonic GABAA 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.
Key words: tonic; GABA; epilepsy; GABAA receptors; hippocampus; 5
Received March 21, 2005;
revised September 15, 2005;
accepted September 19, 2005.
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