title: Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus.
abstract: 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 alpha5-subunit-containing GABAA receptors (alpha5GABAARs). 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 alpha5GABAARs 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 GABAA receptors predominates. In epileptic tissue, alpha5GABAARs 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 alpha5GABAARs 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.
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Scimemi
authors.forename: Alexey
authors.initials: A
authors.lastname: Semyanov
authors.forename: Günther
authors.initials: G
authors.lastname: Sperk
authors.forename: Dimitri M
authors.initials: DM
authors.lastname: Kullmann
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004347:Drug Interactions; D004827:Epilepsy / Q000139:chemically induced* / Q000503:physiopathology; D018682:GABA Agents / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018682:GABA Agents; D018756:GABA Antagonists; D007093:Imidazoles; D009557:Nipecotic Acids; D010852:Picrotoxin; D011963:Receptors, GABA-A; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C105490:L 655,708; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid