title: A functional role for both -aminobutyric acid (GABA) transporter-1 and GABA transporter-3 in the modulation of extracellular GABA and GABAergic tonic conductances in the rat hippocampus.
abstract: Tonic γ-aminobutyric acid (GABA)A receptor-mediated signalling controls neuronal network excitability in the hippocampus. Although the extracellular concentration of GABA (e[GABA]) is critical in determining tonic conductances, knowledge on how e[GABA] is regulated by different GABA transporters (GATs) in vivo is limited. Therefore, we studied the role of GATs in the regulation of hippocampal e[GABA] using in vivo microdialysis in freely moving rats. Here we show that GAT-1, which is predominantly presynaptically located, is the major GABA transporter under baseline, quiescent conditions. Furthermore, a significant contribution of GAT-3 in regulating e[GABA] was revealed by administration of the GAT-3 inhibitor SNAP-5114 during simultaneous blockade of GAT-1 by NNC-711. Thus, the GABA transporting activity of GAT-3 (the expression of which is confined to astrocytes) is apparent under conditions in which GAT-1 is blocked. However, sustained neuronal activation by K(+)-induced depolarization caused a profound spillover of GABA into the extrasynaptic space and this increase in e[GABA] was significantly potentiated by sole blockade of GAT-3 (i.e. even when uptake of GAT-1 is intact). Furthermore, experiments using tetrodotoxin to block action potentials revealed that GAT-3 regulates extrasynaptic GABA levels from action potential-independent sources when GAT-1 is blocked. Importantly, changes in e[GABA] resulting from both GAT-1 and GAT-3 inhibition directly precipitate changes in tonic conductances in dentate granule cells as measured by whole-cell patch-clamp recording. Thus, astrocytic GAT-3 contributes to the regulation of e[GABA] in the hippocampus in vivo and may play an important role in controlling the excitability of hippocampal cells when network activity is increased.
authors: Neurobiology of Stress and Behaviour Research Group, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK.
authors: Flavie
authors: F
authors: Kersanté
authors: Samuel C S
authors: SC
authors: Rowley
authors: Ivan
authors: I
authors: Pavlov
authors: María
authors: M
authors: Gutièrrez-Mecinas
authors: Alexey
authors: A
authors: Semyanov
authors: Johannes M H M
authors: JM
authors: Reul
authors: Matthew C
authors: MC
authors: Walker
authors: Astrid C E
authors: AC
authors: Linthorst
mesh_terms: D000200:Action Potentials; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D011188:Potassium / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493417:Slc6a11 protein, rat; D005680:gamma-Aminobutyric Acid; D011188:Potassium
references: Nat Neurosci. 2003 May;6(5):484-90
references: 12679782
references: Brain Res Mol Brain Res. 1995 Oct;33(1):7-21
references: 8774941
references: BMC Biol. 2012 Mar 15;10:26
references: 22420899
references: Nature. 2010 Nov 11;468(7321):305-9
references: 21048709
references: Nat Med. 2009 Dec;15(12):1392-8
references: 19966779
references: Nat Commun. 2011 Jul 05;2:376
references: 21730957
references: Neuron. 2007 Dec 6;56(5):851-65
references: 18054861
references: Neuropsychopharmacology. 2010 Jul;35(8):1625-52
references: 20410874
references: Neuropharmacology. 2000 Sep;39(12):2399-407
references: 10974324
references: Endocrinology. 2008 Jul;149(7):3244-53
references: 18356272
references: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references: 15738957
references: PLoS One. 2009 Sep 24;4(9):e7153
references: 19777062
references: Recept Channels. 1995;3(2):129-46
references: 8581400
references: Science. 2010 Nov 5;330(6005):790-6
references: 20929730
references: Recept Channels. 1994;2(3):207-13
references: 7874447
references: Endocrinology. 1994 Aug;135(2):520-32
references: 7518383
references: Exp Neurol. 2012 Jan;233(1):3-11
references: 21466804
references: Trends Neurosci. 2004 May;27(5):262-9
references: 15111008
references: Neuroscience. 2011 Oct 27;194:208-19
references: 21840377
references: Hippocampus. 2003;13(7):806-15
references: 14620876
references: Neurochem Int. 1996 Oct;29(4):335-56
references: 8939442
references: J Neurophysiol. 2005 Aug;94(2):990-1000
references: 15829599
references: J Neurosci Methods. 1995 Mar;57(1):93-9
references: 7791370
references: Neuron. 2012 Jan 12;73(1):23-34
references: 22243744
references: J Neurophysiol. 2002 May;87(5):2624-8
references: 11976398
references: Neuropharmacology. 2013 Jun;69:55-61
references: 22538087
references: Endocrinology. 2011 Apr;152(4):1551-61
references: 21285326
references: Results Probl Cell Differ. 2008;44:29-48
references: 17671772
references: Neuroscience. 2007 Sep 7;148(3):794-805
references: 17693036
references: Prog Neurobiol. 2008 Nov;86(3):297-303
references: 18786601
references: J Neurophysiol. 2003 Sep;90(3):1363-74
references: 12966170
references: J Neurophysiol. 2002 Dec;88(6):2899-908
references: 12466416
references: Front Neurosci. 2012 Jan 11;5:148
references: 22275879
references: J Neurochem. 2008 Jun;105(5):1781-93
references: 18248614
references: Nat Neurosci. 2011 Dec 11;15(1):70-80
references: 22158513
references: J Neurosci. 2007 Jul 11;27(28):7520-31
references: 17626213
references: J Physiol. 2003 Apr 1;548(Pt 1):97-110
references: 12588900
references: J Neurophysiol. 2003 Oct;90(4):2690-701
references: 12815026
references: Curr Opin Neurobiol. 2012 Jun;22(3):552-8
references: 22036769
references: J Comp Neurol. 1996 Apr 15;367(4):595-606
references: 8731228
references: Mol Pharmacol. 2003 Jan;63(1):2-8
references: 12488530