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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 GABA_A 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 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 5-subunit-containing GABA_A receptors (5GABA_ARs). 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 5GABA_ARs 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 GABA_A receptors predominates. In epileptic tissue, 5GABA_ARs 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 5GABA_ARs 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.

Key words: tonic; GABA; epilepsy; GABA_A receptors; hippocampus; 5

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Received March 21, 2005; revised September 15, 2005; accepted September 19, 2005.

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