title: GABA-independent GABAA receptor openings maintain tonic currents.
abstract: Activation of GABA(A) receptors (GABA(A)Rs) produces two forms of inhibition: phasic inhibition generated by the rapid, transient activation of synaptic GABA(A)Rs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of perisynaptic or extrasynaptic GABA(A)Rs, which can detect extracellular GABA. Such tonic GABA(A)R-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABA(A) receptor openings. This tonic GABA(A)R conductance is resistant to the competitive GABA(A)R antagonist SR95531 (gabazine), which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker, picrotoxin. When slices are perfused with 200 nm GABA, a concentration that is comparable to CSF concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABA(A)Rs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations.
authors: UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors: Agnieszka I
authors: AI
authors: Wlodarczyk
authors: Sergiy
authors: S
authors: Sylantyev
authors: Murray B
authors: MB
authors: Herd
authors: Flavie
authors: F
authors: Kersanté
authors: Jeremy J
authors: JJ
authors: Lambert
authors: Dmitri A
authors: DA
authors: Rusakov
authors: Astrid C E
authors: AC
authors: Linthorst
authors: Alexey
authors: A
authors: Semyanov
authors: Delia
authors: D
authors: Belelli
authors: Ivan
authors: I
authors: Pavlov
authors: Matthew C
authors: MC
authors: Walker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055592:Biophysical Phenomena / Q000187:drug effects / Q000502:physiology*; D001703:Biophysics; D002851:Chromatography, High Pressure Liquid; D018891:Dentate Gyrus / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018755:GABA Agonists; D018756:GABA Antagonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid