title: A reinforcing circuit action of extrasynaptic GABAA receptor modulators on cerebellar granule cell inhibition.
abstract: GABAA receptors (GABARs) are the targets of a wide variety of modulatory drugs which enhance chloride flux through GABAR ion channels. Certain GABAR modulators appear to acutely enhance the function of δ subunit-containing GABAR subtypes responsible for tonic forms of inhibition. Here we identify a reinforcing circuit mechanism by which these drugs, in addition to directly enhancing GABAR function, also increase GABA release. Electrophysiological recordings in cerebellar slices from rats homozygous for the ethanol-hypersensitive (α6100Q) allele show that modulators and agonists selective for δ-containing GABARs such as THDOC, ethanol and THIP (gaboxadol) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in granule cells. Ethanol fails to augment granule cell sIPSC frequency in the presence of glutamate receptor antagonists, indicating that circuit mechanisms involving granule cell output contribute to ethanol-enhancement of synaptic inhibition. Additionally, GABAR antagonists decrease ethanol-induced enhancement of Golgi cell firing. Consistent with a role for glutamatergic inputs, THIP-induced increases in Golgi cell firing are abolished by glutamate receptor antagonists. Moreover, THIP enhances the frequency of spontaneous excitatory postsynaptic currents in Golgi cells. Analyses of knockout mice indicate that δ subunit-containing GABARs are required for enhancing GABA release in the presence of ethanol and THIP. The limited expression of the GABAR δ subunit protein within the cerebellar cortex suggests that an indirect, circuit mechanism is responsible for stimulating Golgi cell GABA release by drugs selective for extrasynaptic isoforms of GABARs. Such circuit effects reinforce direct actions of these positive modulators on tonic GABAergic inhibition and are likely to contribute to the potent effect of these compounds as nervous system depressants.
authors: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America. santhavi@njms.rutgers.edu
authors: Vijayalakshmi
authors: V
authors: Santhakumar
authors: Pratap
authors: P
authors: Meera
authors: Movses H
authors: MH
authors: Karakossian
authors: Thomas S
authors: TS
authors: Otis
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002531:Cerebellum / Q000166:cytology*; D000431:Ethanol / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D005971:Glutamates / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D005971:Glutamates; D007555:Isoxazoles; D021122:Protein Subunits; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol
references: J Neurophysiol. 2013 Apr;109(7):1746-63
references: 23324316
references: J Physiol. 1998 Aug 1;510 ( Pt 3):845-66
references: 9660898
references: Nat Neurosci. 2002 Aug;5(8):721-2
references: 12118257
references: Alcohol Clin Exp Res. 2007 Jan;31(1):89-99
references: 17207106
references: Alcohol. 2007 May;41(3):177-85
references: 17521848
references: Eur J Pharmacol. 1992 Feb 18;211(3):427-8
references: 1319916
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14439-44
references: 14623958
references: Cerebellum. 2012 Mar;11(1):121-31
references: 20049574
references: J Neurosci. 2004 Sep 29;24(39):8454-8
references: 15456818
references: Alcohol. 2003 Aug-Oct;31(1-2):93-7
references: 14615016
references: Brain Res. 1992 Oct 2;592(1-2):255-60
references: 1360312
references: Br J Pharmacol. 2002 Aug;136(7):965-74
references: 12145096
references: J Neurosci. 2006 Mar 22;26(12):3357-64
references: 16554486
references: Neuropharmacology. 1999 Sep;38(9):1273-9
references: 10471080
references: J Neurosci. 2006 Feb 8;26(6):1749-58
references: 16467523
references: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8546-51
references: 16581914
references: J Neurosci. 1998 Mar 1;18(5):1693-703
references: 9464994
references: Neuropharmacology. 2001 Nov;41(6):730-6
references: 11640927
references: Alcohol. 2007 May;41(3):211-21
references: 17591544
references: Neuroscience. 2010 May 19;167(3):644-55
references: 20206233
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15218-23
references: 14625373
references: Mol Pharmacol. 2001 Apr;59(4):814-24
references: 11259626
references: J Pharmacol Exp Ther. 2008 Mar;324(3):1127-35
references: 18094320
references: Neuron. 2012 Jan 12;73(1):23-34
references: 22243744
references: J Neurophysiol. 2003 Feb;89(2):806-13
references: 12574458
references: J Neurosci. 2004 Sep 22;24(38):8379-82
references: 15385620
references: J Biol Chem. 2001 Mar 30;276(13):10532-8
references: 11136737
references: J Neurophysiol. 2007 May;97(5):3806-11
references: 17376852
references: J Physiol. 2007 May 1;580(Pt.3):731-43
references: 17303643
references: J Physiol. 1996 Dec 15;497 ( Pt 3):753-9
references: 9003560
references: Eur J Pharmacol. 2001 Jun 1;421(1):31-8
references: 11408046
references: Neuropsychopharmacology. 2010 Aug;35(9):1984-96
references: 20520600
references: Nat Neurosci. 2005 Mar;8(3):339-45
references: 15696164
references: Nat Rev Neurosci. 2008 May;9(5):370-86
references: 18425091
references: J Pharmacol Exp Ther. 2008 Jan;324(1):399-400; author reply 401-3
references: 18094322
references: Neuron. 2012 Jan 12;73(1):149-58
references: 22243753
references: Science. 2007 Nov 2;318(5851):815-7
references: 17975069
references: J Neurosci. 2004 Apr 14;24(15):3746-51
references: 15084654
references: J Neurophysiol. 2012 Jun;107(11):2958-70
references: 22378171
references: J Pharmacol Exp Ther. 2007 Nov;323(2):684-91
references: 17704355
references: J Pharmacol Exp Ther. 2006 Mar;316(3):1360-8
references: 16272217
references: J Neurosci. 2011 Jan 12;31(2):753-63
references: 21228184
references: J Neurosci. 2007 Aug 22;27(34):9022-31
references: 17715339
references: Nature. 1993 Jan 28;361(6410):356-9
references: 7678923
references: Nature. 2004 Apr 22;428(6985):856-60
references: 15103377
references: J Neurosci. 2011 Jan 12;31(2):565-74
references: 21228165
references: Trends Neurosci. 2010 Jul;33(7):299-306
references: 20409596
references: J Neurophysiol. 2007 Mar;97(3):2293-300
references: 17215511
references: Nature. 1977 Jul 7;268(5615):53-5
references: 196200
references: J Neurophysiol. 2011 Oct;106(4):2057-64
references: 21795619
references: J Neurosci. 2003 Jan 15;23(2):367-72
references: 12533595
references: Eur J Neurosci. 1997 Mar;9(3):533-48
references: 9104595
references: J Neurosci. 2012 Feb 15;32(7):2523-37
references: 22396425
references: J Neurophysiol. 2011 Jun;105(6):2931-6
references: 21471393
references: Nature. 2001 Jan 4;409(6816):88-92
references: 11343119
references: Alcohol Clin Exp Res. 2012 Apr;36(4):616-24
references: 22004123
references: Nat Neurosci. 2007 Jan;10(1):40-8
references: 17159992
references: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8540-5
references: 16698930
references: J Neurophysiol. 2004 Sep;92(3):1658-67
references: 15140905
references: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references: 15738957
references: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12905-10
references: 10536021
references: Brain Res Mol Brain Res. 2001 Mar 5;87(2):263-70
references: 11245930
references: J Neurophysiol. 2004 Sep;92(3):1558-65
references: 15152021
references: J Neurochem. 1998 Oct;71(4):1777-80
references: 9751216
references: Exp Brain Res. 1966;1(1):1-16
references: 5910941
references: Alcohol. 2007 May;41(3):187-99
references: 17521847
references: J Neurosci. 2012 Mar 14;32(11):3887-97
references: 22423109
references: Sleep Med. 2008 May;9(4):393-402
references: 17765013
references: Neuroscience. 2000;101(4):815-50
references: 11113332