title: Functional role of ambient GABA in refining neuronal circuits early in postnatal development.
abstract: Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of "ambient" GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses.
authors: Department of Neuroscience Scuola Internazionale Superiore di Studi Avanzati Trieste, Italy.
authors: Giada
authors: G
authors: Cellot
authors: Enrico
authors: E
authors: Cherubini
mesh_terms: D000367:Age Factors; D000818:Animals; D006801:Humans; D009415:Nerve Net / Q000254:growth & development*; D009474:Neurons / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid
keywords: development; extrasynaptic GABAA receptor; hippocampus; network activity; tonic GABAA conductance
references: J Physiol. 2004 Jun 15;557(Pt 3):829-41
references: 15090604
references: J Neurosci. 2004 Sep 1;24(35):7623-31
references: 15342728
references: Science. 2001 Aug 10;293(5532):1159-63
references: 11498596
references: Nature. 1999 Jan 21;397(6716):251-5
references: 9930699
references: Eur J Neurosci. 2007 Feb;25(3):717-22
references: 17298599
references: Science. 1990 Dec 7;250(4986):1429-32
references: 2147780
references: J Neurosci. 2006 Nov 8;26(45):11720-5
references: 17093093
references: J Physiol. 2008 Dec 1;586(23):5665-78
references: 18832421
references: Nat Neurosci. 2003 May;6(5):484-90
references: 12679782
references: J Neurosci. 2008 May 21;28(21):5547-58
references: 18495889
references: Neuron. 2009 Mar 26;61(6):820-38
references: 19323993
references: J Neurosci. 2005 Dec 14;25(50):11513-20
references: 16354909
references: Neuron. 1997 Feb;18(2):243-55
references: 9052795
references: Eur J Neurosci. 2010 Oct;32(8):1310-8
references: 20846324
references: Prog Biophys Mol Biol. 2005 Jan;87(1):3-16
references: 15471587
references: Eur J Neurosci. 2010 Oct;32(8):1300-9
references: 20846322
references: Eur J Neurosci. 2005 Jul;22(1):107-18
references: 16029200
references: Trends Neurosci. 2005 Mar;28(3):133-9
references: 15749166
references: Physiol Rev. 2007 Oct;87(4):1215-84
references: 17928584
references: Trends Neurosci. 2004 May;27(5):262-9
references: 15111008
references: Neuron. 2002 Dec 19;36(6):1051-61
references: 12495621
references: J Neurosci. 2005 May 11;25(19):4755-65
references: 15888651
references: J Physiol. 2009 May 1;587(Pt 9):1873-9
references: 19153158
references: Front Cell Neurosci. 2010 Mar 31;4:10
references: 20407586
references: Curr Top Dev Biol. 2005;69:215-37
references: 16243601
references: Trends Neurosci. 1997 Nov;20(11):523-9
references: 9364667
references: J Neurosci. 2005 Jun 1;25(22):5280-9
references: 15930375
references: J Neurosci. 2009 Mar 18;29(11):3419-30
references: 19295148
references: Front Cell Neurosci. 2010 Jul 14;4:
references: 20725525
references: Cereb Cortex. 2000 Sep;10(9):899-909
references: 10982750
references: Br J Pharmacol. 1997 Mar;120(5):741-8
references: 9138676
references: J Physiol. 1989 Sep;416:303-25
references: 2575165
references: Neuroscience. 2010 May 19;167(3):644-55
references: 20206233
references: Brain Res. 2007 Dec;1186:56-64
references: 17996219
references: Eur J Neurosci. 2008 May;27(9):2402-12
references: 18430034
references: Neurochem Res. 2003 Feb;28(2):347-52
references: 12608708
references: Nat Med. 2005 Nov;11(11):1205-13
references: 16227993
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: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13176-81
references: 17656555
references: Neuron. 2006 Jan 5;49(1):131-42
references: 16387645
references: Nat Rev Neurosci. 2002 Sep;3(9):715-27
references: 12209120
references: Neuron. 2003 Aug 28;39(5):807-20
references: 12948447
references: J Neurophysiol. 2000 Sep;84(3):1392-403
references: 10980012
references: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3662-7
references: 14993607
references: J Physiol. 2008 Nov 15;586(22):5437-53
references: 18801845
references: J Neurosci. 1992 Nov;12(11):4151-72
references: 1331359
references: J Physiol. 1996 Dec 15;497 ( Pt 3):753-9
references: 9003560
references: J Physiol. 1995 Jun 1;485 ( Pt 2):419-35
references: 7545231
references: J Neurosci. 2002 May 15;22(10):RC223
references: 12006605
references: Cereb Cortex. 2003 Jun;13(6):684-92
references: 12764045
references: J Neurosci. 2004 Jun 30;24(26):5877-80
references: 15229234
references: Curr Opin Neurobiol. 2007 Feb;17(1):81-6
references: 17234400
references: Front Synaptic Neurosci. 2010 Feb 22;2:1
references: 21423487
references: Neuroscientist. 2012 Oct;18(5):467-86
references: 22547529
references: J Biol Chem. 2012 Jun 15;287(25):20839-50
references: 22544747
references: J Neurosci. 2006 Jan 11;26(2):597-608
references: 16407558
references: Nature. 2006 Feb 2;439(7076):589-93
references: 16341203
references: Nat Commun. 2011 Jul 05;2:376
references: 21730957
references: Nat Rev Neurosci. 2002 Sep;3(9):728-39
references: 12209121
references: Nature. 1995 Nov 2;378(6552):75-8
references: 7477292
references: Korean J Physiol Pharmacol. 2010 Dec;14(6):399-405
references: 21311681
references: J Neurosci. 2012 May 9;32(19):6688-98
references: 22573691
references: J Neurochem. 2008 Jun;105(5):1781-93
references: 18248614
references: Science. 2008 Jul 4;321(5885):53-7
references: 18599766
references: Cereb Cortex. 2011 Mar;21(3):574-87
references: 20624842
references: Nat Rev Neurosci. 2008 May;9(5):331-43
references: 18382465
references: Trends Neurosci. 2001 Mar;24(3):155-62
references: 11182455
references: Cereb Cortex. 2007 Aug;17(8):1782-7
references: 16997904
references: Science. 2009 Dec 4;326(5958):1419-24
references: 19965761
references: J Physiol. 2008 Feb 15;586(4):965-87
references: 18063661
references: J Neurosci. 2008 Jan 30;28(5):1185-97
references: 18234896
references: J Neurosci. 2001 Apr 15;21(8):2630-9
references: 11306616
references: Trends Neurosci. 1991 Dec;14(12):515-9
references: 1726341
references: J Neurosci. 1999 Dec 1;19(23):10372-82
references: 10575034
references: Eur J Neurosci. 1997 Mar;9(3):533-48
references: 9104595
references: J Neurosci Res. 2000 Dec 1;62(5):638-43
references: 11104502
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14439-44
references: 14623958
references: J Neurosci. 2009 May 27;29(21):6982-8
references: 19474325
references: Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3967-72
references: 15007179
references: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references: 15738957
references: Neuron. 2011 Aug 25;71(4):695-709
references: 21867885
references: J Neurosci. 2007 May 9;27(19):5224-35
references: 17494709
references: Front Cell Neurosci. 2011 Jul 28;5:15
references: 21847370
references: J Neurosci. 1995 Nov;15(11):7734-46
references: 7472524
references: Cell Tissue Res. 2001 Aug;305(2):187-202
references: 11545256
references: Neuron. 1993 Sep;11(3):401-7
references: 8104430
references: Neuron. 2011 May 12;70(3):385-409
references: 21555068
references: J Neurosci. 2008 Feb 6;28(6):1421-6
references: 18256262
references: Neuron. 1995 Dec;15(6):1287-98
references: 8845153