title: An evolutionarily conserved switch in response to GABA affects development and behavior of the locomotor circuit of Caenorhabditis elegans.
abstract: The neurotransmitter gamma-aminobutyric acid (GABA) is depolarizing in the developing vertebrate brain, but in older animals switches to hyperpolarizing and becomes the major inhibitory neurotransmitter in adults. We discovered a similar developmental switch in GABA response in Caenorhabditis elegans and have genetically analyzed its mechanism and function in a well-defined circuit. Worm GABA neurons innervate body wall muscles to control locomotion. Activation of GABAA receptors with their agonist muscimol in newly hatched first larval (L1) stage animals excites muscle contraction and thus is depolarizing. At the mid-L1 stage, as the GABAergic neurons rewire onto their mature muscle targets, muscimol shifts to relaxing muscles and thus has switched to hyperpolarizing. This muscimol response switch depends on chloride transporters in the muscles analogous to those that control GABA response in mammalian neurons: the chloride accumulator sodium-potassium-chloride-cotransporter-1 (NKCC-1) is required for the early depolarizing muscimol response, while the two chloride extruders potassium-chloride-cotransporter-2 (KCC-2) and anion-bicarbonate-transporter-1 (ABTS-1) are required for the later hyperpolarizing response. Using mutations that disrupt GABA signaling, we found that neural circuit development still proceeds to completion but with an ∼6-hr delay. Using optogenetic activation of GABAergic neurons, we found that endogenous GABAA signaling in early L1 animals, although presumably depolarizing, does not cause an excitatory response. Thus a developmental depolarizing-to-hyperpolarizing shift is an ancient conserved feature of GABA signaling, but existing theories for why this shift occurs appear inadequate to explain its function upon rigorous genetic analysis of a well-defined neural circuit.
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520.
authors: Bingjie
authors: B
authors: Han
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520.
authors: Andrew
authors: A
authors: Bellemer
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520 michael.koelle@yale.edu.
authors: Michael R
authors: MR
authors: Koelle
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008124:Locomotion; D008564:Membrane Potentials; D009118:Muscimol / Q000494:pharmacology; D009154:Mutation; D011963:Receptors, GABA-A / Q000378:metabolism*; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D027321:Anion Transport Proteins; D029742:Caenorhabditis elegans Proteins; D058785:GABA-A Receptor Agonists; D009118:Muscimol; D011963:Receptors, GABA-A; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C551533:ABTS-1 protein, C elegans
keywords: GABA response; inhibitory; signaling; switch
references: EMBO J. 2011 May 4;30(9):1852-63
references: 21427702
references: Nature. 2006 Feb 2;439(7076):589-93
references: 16341203
references: Eur J Neurosci. 2002 Jul;16(2):197-208
references: 12169102
references: J Neurophysiol. 1996 Aug;76(2):1074-88
references: 8871221
references: J Neurophysiol. 1992 Jul;68(1):197-212
references: 1381418
references: Cereb Cortex. 2003 Jun;13(6):684-92
references: 12764045
references: Brain Res Mol Brain Res. 1998 Jul 15;58(1-2):103-11
references: 9685599
references: Brain Res. 1978 Apr 7;144(1):179-84
references: 638760
references: J Physiol. 2010 Jul 15;588(Pt 14):2557-69
references: 20498234
references: Nature. 1998 Feb 19;391(6669):806-11
references: 9486653
references: Physiol Rev. 2007 Oct;87(4):1215-84
references: 17928584
references: Science. 2014 Feb 7;343(6171):670-5
references: 24503855
references: J Neurosci. 2000 Jun 1;20(11):3964-72
references: 10818131
references: Nature. 1998 Sep 3;395(6697):78-82
references: 9738501
references: Genetics. 1974 May;77(1):71-94
references: 4366476
references: Neuron. 2012 Feb 9;73(3):453-65
references: 22325199
references: Front Pharmacol. 2012 Apr 19;3:65
references: 22529813
references: Neural Dev. 2012;7:7
references: 22314215
references: J Neurobiol. 1997 Nov 20;33(6):781-95
references: 9369151
references: Nat Methods. 2008 Oct;5(10):895-902
references: 18794862
references: J Neurosci. 2003 Jan 15;23(2):518-29
references: 12533612
references: J Neurosci. 1999 Jul 1;19(13):5348-59
references: 10377345
references: Philos Trans R Soc Lond B Biol Sci. 1976 Aug 10;275(938):327-48
references: 8806
references: Genetics. 2005 Feb;169(2):651-70
references: 15489511
references: Philos Trans R Soc Lond B Biol Sci. 1986 Nov 12;314(1165):1-340
references: 22462104
references: J Neurosci. 2003 Apr 1;23(7):2591-9
references: 12684444
references: J Neurosci Methods. 2008 May 15;170(1):67-76
references: 18279971
references: Neuron. 2006 Jan 5;49(1):81-94
references: 16387641
references: EMBO J. 1991 Dec;10(12):3959-70
references: 1935914
references: Nature. 1994 Dec 22-29;372(6508):780-3
references: 7997265
references: J Neurosci. 2000 Oct 15;20(20):7531-8
references: 11027211
references: J Neurophysiol. 1999 Apr;81(4):1939-48
references: 10200228
references: Nature. 1993 Jul 22;364(6435):337-41
references: 8332191
references: Nature. 1999 Jan 21;397(6716):251-5
references: 9930699
references: Adv Parasitol. 1975;13:71-122
references: 1169872
references: J Neurophysiol. 2001 Jan;85(1):425-34
references: 11152743
references: J Neurosci. 2012 Sep 26;32(39):13630-8
references: 23015452
references: Life Sci. 1988;43(21):1701-6
references: 2848169
references: Gene. 1990 Sep 14;93(2):189-98
references: 2121610
references: J Neurosci. 2008 Jul 9;28(28):7104-12
references: 18614679
references: J Neurosci. 2009 Aug 12;29(32):9943-54
references: 19675228
references: Neuron. 2011 May 26;70(4):742-57
references: 21609829
references: J Neurosci. 1999 Jan 15;19(2):539-48
references: 9880574
references: Neuron. 2009 Mar 26;61(6):820-38
references: 19323993
references: Trends Neurosci. 2004 Jul;27(7):407-14
references: 15219740
references: Front Cell Neurosci. 2012 Aug 28;6:35
references: 22973192
references: Nature. 1993 Jul 22;364(6435):334-7
references: 8332190
references: J Neurophysiol. 2011 Aug;106(2):817-27
references: 21613582
references: J Neurosci. 1999 Dec 1;19(23):10372-82
references: 10575034
references: J Physiol. 1989 Sep;416:303-25
references: 2575165
references: J Neurosci. 2006 May 10;26(19):5117-30
references: 16687503
references: J Physiol. 2004 Jun 15;557(Pt 3):829-41
references: 15090604
references: J Physiol. 2005 Aug 1;566(Pt 3):671-9
references: 15961425
references: Nature. 1992 Feb 27;355(6363):838-41
references: 1538764
references: Nat Neurosci. 2003 Nov;6(11):1145-52
references: 14555952
references: J Neurosci. 2007 May 9;27(19):5224-35
references: 17494709