title: GABA(A) receptor-mediated signaling alters the structure of spontaneous activity in the developing retina.
abstract: Ambient GABA modulates firing patterns in adult neural circuits by tonically activating extrasynaptic GABA(A) receptors. Here, we demonstrate that during a developmental period when activation of GABA(A) receptors causes membrane depolarization, tonic activation of GABA(A) receptors blocks all spontaneous activity recorded in retinal ganglion cells (RGCs) and starburst amacrine cells (SACs). Bath application of the GABA(A) receptor agonist muscimol blocked spontaneous correlated increases in intracellular calcium concentration and compound postsynaptic currents in RGCs associated with retinal waves. In addition, GABA(A) receptor agonists activated a tonic current in RGCs that significantly reduced their excitability. Using a transgenic mouse in which green fluorescent protein is expressed under the metabotropic glutamate receptor subtype 2 promoter to target recordings from SACs, we found that GABA(A) receptor agonists blocked compound postsynaptic currents and also activated a tonic current. GABA(A) receptor antagonists reduced the holding current in SACs but not RGCs, indicating that ambient levels of GABA tonically activate GABA(A) receptors in SACs. GABA(A) receptor antagonists did not block retinal waves but did alter the frequency and correlation structure of spontaneous RGC firing. Interestingly, the drug aminophylline, a general adenosine receptor antagonist used to block retinal waves, induced a tonic GABA(A) receptor antagonist-sensitive current in outside-out patches excised from RGCs, indicating that aminophylline exerts its action on retinal waves by direct activation of GABA(A) receptors. These findings have implications for how various neuroactive drugs and neurohormones known to modulate extrasynaptic GABA(A) receptors may influence spontaneous firing patterns that are critical for the establishment of adult neural circuits.
authors: Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.
authors: Chih-Tien
authors: CT
authors: Wang
authors: Aaron G
authors: AG
authors: Blankenship
authors: Anastasia
authors: A
authors: Anishchenko
authors: Justin
authors: J
authors: Elstrott
authors: Michael
authors: M
authors: Fikhman
authors: Shigetada
authors: S
authors: Nakanishi
authors: Marla B
authors: MB
authors: Feller
mesh_terms: D025042:Amacrine Cells / Q000187:drug effects / Q000502:physiology; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004347:Drug Interactions; D018682:GABA Agents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D012160:Retina / Q000166:cytology* / Q000254:growth & development*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology; D014795:Visual Pathways / Q000187:drug effects / Q000502:physiology*
chemical_list: D018682:GABA Agents; D010726:Phosphodiesterase Inhibitors; D011963:Receptors, GABA-A; D049452:Green Fluorescent Proteins; D000628:Aminophylline
references: J Neurophysiol. 2003 Jul;90(1):165-74
references: 12843308
references: Neuron. 2003 Dec 18;40(6):1147-60
references: 14687549
references: Dev Neurosci. 2004;26(5-6):406-16
references: 15855770
references: Neuron. 2001 Jun;30(3):771-80
references: 11430810
references: J Comp Neurol. 1998 Apr 13;393(3):309-19
references: 9548552
references: Neurochem Res. 2001 Sep;26(8-9):907-13
references: 11699942
references: Neuron. 2004 Dec 2;44(5):851-64
references: 15572115
references: Trends Neurosci. 2004 Sep;27(9):569-75
references: 15331240
references: Neuron. 2002 Aug 15;35(4):773-82
references: 12194875
references: J Physiol. 2005 Jan 1;562(Pt 1):37-46
references: 15528237
references: Vision Res. 1998 May;38(10):1411-30
references: 9667008
references: J Neurophysiol. 2002 Nov;88(5):2311-21
references: 12424272
references: Trends Neurosci. 2003 Apr;26(4):199-206
references: 12689771
references: Nat Neurosci. 2003 May;6(5):484-90
references: 12679782
references: Neuron. 1997 Feb;18(2):243-55
references: 9052795
references: Neuron. 2005 Sep 15;47(6):803-15
references: 16157276
references: J Neurosci. 2005 Aug 10;25(32):7309-16
references: 16093380
references: Trends Neurosci. 2004 May;27(5):262-9
references: 15111008
references: J Neurosci. 2003 Jul 16;23(15):6272-9
references: 12867512
references: Neuron. 1993 Nov;11(5):923-38
references: 8240814
references: Neuron. 2002 Dec 19;36(6):1051-61
references: 12495621
references: Mol Pharmacol. 2007 Feb;71(2):539-48
references: 17090706
references: Science. 1996 May 24;272(5265):1182-7
references: 8638165
references: J Neurosci. 2001 Nov 1;21(21):8514-22
references: 11606640
references: Trends Neurosci. 2004 Jul;27(7):422-7
references: 15219742
references: Pharmacol Ther. 2006 Sep;111(3):533-54
references: 16427127
references: Pharmacol Biochem Behav. 2005 Sep;82(1):241-5
references: 16185759
references: Curr Opin Neurobiol. 2007 Feb;17(1):73-80
references: 17254766
references: J Neurosci. 1998 May 15;18(10):3767-78
references: 9570807
references: J Neurosci. 2005 Dec 14;25(50):11553-63
references: 16354913
references: J Physiol. 2007 Jun 1;581(Pt 2):515-28
references: 17317750
references: Neurosci Lett. 1982 Mar 17;29(1):57-61
references: 7070713
references: Nat Rev Neurosci. 2002 Sep;3(9):715-27
references: 12209120
references: Prog Brain Res. 2001;131:599-613
references: 11420974
references: J Neurosci. 1998 Jun 1;18(11):4155-65
references: 9592095
references: Science. 2006 Dec 8;314(5805):1610-3
references: 17158331
references: Trends Neurosci. 2001 Jun;24(6):353-60
references: 11356508
references: Neuron. 1996 Jun;16(6):1087-95
references: 8663985
references: Addict Biol. 2004 Jun;9(2):153-7; discussion 159-60
references: 15223541
references: J Physiol. 1996 Dec 15;497 ( Pt 3):753-9
references: 9003560
references: J Neurosci. 1999 May 1;19(9):3580-93
references: 10212317
references: J Physiol. 1995 Jun 1;485 ( Pt 2):419-35
references: 7545231
references: J Neurosci Methods. 1994 Jan;51(1):95-106
references: 8189755
references: Science. 2007 Jan 19;315(5810):390-3
references: 17234950
references: J Physiol. 2004 Oct 15;560(Pt 2):533-49
references: 15308679
references: Trends Neurosci. 2005 Jun;28(6):278-83
references: 15927682
references: Prog Neurobiol. 2005 Jul;76(4):213-35
references: 16280194
references: Curr Opin Neurobiol. 1999 Feb;9(1):94-104
references: 10072366
references: J Neurophysiol. 2006 Apr;95(4):2404-16
references: 16371454
references: J Neurosci. 2001 Nov 1;21(21):8664-71
references: 11606654
references: Nat Rev Neurosci. 2002 Sep;3(9):728-39
references: 12209121
references: Nature. 1995 Nov 2;378(6552):75-8
references: 7477292
references: J Physiol. 1998 Feb 15;507 ( Pt 1):219-36
references: 9490842
references: J Neurosci. 2001 Feb 1;21(3):897-910
references: 11157076
references: Prog Brain Res. 2005;147:115-24
references: 15581701
references: J Neurophysiol. 1994 Apr;71(4):1318-35
references: 8035217
references: Annu Rev Neurosci. 1999;22:29-47
references: 10202531
references: Neurosci Lett. 1993 Nov 26;163(1):71-3
references: 8295736
references: Trends Neurosci. 2003 Dec;26(12):676-82
references: 14624852
references: Nat Neurosci. 2005 Jan;8(1):72-8
references: 15608630
references: Cell. 1998 Oct 2;95(1):17-27
references: 9778244
references: J Neurosci. 2002 Feb 15;22(4):1248-55
references: 11850452
references: Nature. 2004 Apr 22;428(6985):856-60
references: 15103377
references: J Neurophysiol. 2003 Oct;90(4):2690-701
references: 12815026
references: Nature. 1999 Jan 21;397(6716):251-5
references: 9930699
references: J Neurophysiol. 2004 May;91(5):1999-2009
references: 14681336
references: J Neurosci. 2003 Aug 20;23(20):7621-9
references: 12930801
references: Neuron. 2003 May 8;38(3):433-45
references: 12741990
references: J Neurosci. 2003 Jan 15;23(2):518-29
references: 12533612
references: J Neurosci. 2009 Sep 9;29(36):11237-45
references: 19741130
references: Nat Neurosci. 2006 Mar;9(3):363-71
references: 16462736
references: J Neurophysiol. 2005 Mar;93(3):1317-25
references: 15483067
references: Methods Enzymol. 1992;207:123-31
references: 1528115
references: Neuron. 1999 Nov;24(3):673-85
references: 10595518
references: J Neurosci. 2000 Oct 15;20(20):7672-81
references: 11027228
references: Science. 1991 May 17;252(5008):939-43
references: 2035024
references: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references: 15738957
references: Clin Exp Pharmacol Physiol. 1999 Nov;26(11):941-4
references: 10561821