Calcium-independent inhibitory G-protein signaling induces persistent presynaptic muting of hippocampal synapses.
Adaptive forms of synaptic plasticity that reduce excitatory synaptic transmission in response to prolonged increases in neuronal activity may prevent runaway positive feedback in neuronal circuits. In hippocampal neurons, for example, glutamatergic presynaptic terminals are selectively silenced, creating "mute" synapses, after periods of increased neuronal activity or sustained depolarization. Previous work suggests that cAMP-dependent and proteasome-dependent mechanisms participate in silencing induction by depolarization, but upstream activators are unknown. We, therefore, tested the role of calcium and G-protein signaling in silencing induction in cultured hippocampal neurons. We found that silencing induction by depolarization was not dependent on rises in intracellular calcium, from either extracellular or intracellular sources. Silencing was, however, pertussis toxin sensitive, which suggests that inhibitory G-proteins are recruited. Surprisingly, blocking four common inhibitory G-protein-coupled receptors (GPCRs) (adenosine A(1) receptors, GABA(B) receptors, metabotropic glutamate receptors, and CB(1) cannabinoid receptors) and one ionotropic receptor with metabotropic properties (kainate receptors) failed to prevent depolarization-induced silencing. Activating a subset of these GPCRs (A(1) and GABA(B)) with agonist application induced silencing, however, which supports the hypothesis that G-protein activation is a critical step in silencing. Overall, our results suggest that depolarization activates silencing through an atypical GPCR or through receptor-independent G-protein activation. GPCR agonist-induced silencing exhibited dependence on the ubiquitin-proteasome system, as was shown previously for depolarization-induced silencing, implicating the degradation of vital synaptic proteins in silencing by GPCR activation. These data suggest that presynaptic muting in hippocampal neurons uses a G-protein-dependent but calcium-independent mechanism to depress presynaptic vesicle release.
Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri 63110, USA.
Devon C
DC
Crawford
Chun Yun
CY
Chang
Krzysztof L
KL
Hyrc
Steven
S
Mennerick
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D043682:Receptor, Adenosine A1; D043884:Receptor, Cannabinoid, CB1; D043562:Receptors, G-Protein-Coupled; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
J Neurosci. 1993 Aug;13(8):3439-47
8393482
J Physiol. 1982 Feb;323:211-27
6808119
Anal Chem. 2000 May 1;72(9):2001-7
10815957
Trends Neurosci. 1998 Dec;21(12):521-8
9881850
Cell. 2003 Oct 3;115(1):49-60
14532002
Neuron. 1989 Nov;3(5):583-8
2577129
J Neurophysiol. 2000 Apr;83(4):1787-95
10758091
Handb Exp Pharmacol. 2008;(184):207-60
18064416
Neuron. 2002 Dec 19;36(6):1103-14
12495625
J Neurochem. 2001 Nov;79(3):463-84
11701750
Neuron. 1994 May;12(5):1139-48
8185949
Neuron. 2004 Sep 16;43(6):871-81
15363397
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21936-41
19995977
J Neurochem. 2007 Dec;103(6):2121-35
18070252
J Neurosci. 2010 Feb 3;30(5):1798-809
20130189
Neuron. 1997 Jun;18(6):995-1008
9208866
Hippocampus. 2008;18(3):258-65
18000819
Cell. 2008 Oct 31;135(3):422-35
18984155
Neuron. 2008 Mar 27;57(6):819-26
18367083
J Neurosci. 2004 Nov 24;24(47):10679-86
15564584
J Neurosci. 1991 May;11(5):1375-80
1851219
Trends Pharmacol Sci. 1990 Nov;11(11):462-8
1980041
Cell. 2007 Sep 7;130(5):943-57
17803915
Mol Pharmacol. 1999 Aug;56(2):429-33
10419564
Neuron. 1997 Sep;19(3):473-6
9331339
Acta Physiol Scand. 1979 Jan;105(1):126-8
217240
J Vis Exp. 2010 Jan 04;(35):
20048736
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):846-9
7846064
J Pharmacol Exp Ther. 2002 Dec;303(3):937-44
12438512
J Neurophysiol. 1992 Apr;67(4):1009-13
1350306
J Neurophysiol. 1998 Jul;80(1):270-81
9658049
Brain Res. 2007 Mar 2;1135(1):69-76
17198692
Neuron. 2006 Nov 22;52(4):663-77
17114050
Neurosci Lett. 1991 Sep 2;130(1):128-32
1721110
Stroke. 1997 Jan;28(1):206-10
8996513
J Neurosci. 2003 Mar 1;23(5):1825-31
12629186
J Physiol. 2009 Feb 1;587(3):513-20
19074969
Neuron. 2000 Oct;28(1):183-93
11086993
J Neurosci. 1999 Jan 15;19(2):653-63
9880586
Nature. 1990 Nov 29;348(6300):443-6
2247147
J Neurosci. 2005 Mar 16;25(11):2832-7
15772343
PLoS One. 2009 Dec 04;4(12):e8166
19997638
Neuroscience. 2007 Sep 7;148(3):794-805
17693036
Neuron. 2004 May 13;42(3):423-35
15134639
Neuron. 1992 Nov;9(5):967-75
1419003
Neuron. 1996 Jun;16(6):1197-207
8663996
J Neurosci. 2008 May 14;28(20):5159-68
18480272
Neuropharmacology. 1997 Nov-Dec;36(11-12):1517-32
9517422
Brain Res Mol Brain Res. 2003 Jan 31;110(1):1-6
12573527
Neuron. 2006 May 4;50(3):345-6
16675387
J Neurosci. 2006 Aug 2;26(31):8137-47
16885227
J Neurophysiol. 2009 Mar;101(3):1375-85
19109458
Annu Rev Physiol. 2002;64:355-405
11826273
Neuron. 2010 May 13;66(3):337-51
20471348
Handb Exp Pharmacol. 2009;(193):535-87
19639293
J Physiol. 1970 Mar;206(3):629-44
5498509
Neuron. 1996 Jun;16(6):1147-57
8663991
J Biol Chem. 2002 May 3;277(18):15897-903
11832491
Nature. 2001 Mar 29;410(6828):588-92
11279497
Neurobiol Dis. 1998 Dec;5(6 Pt B):386-404
9974173
Neuron. 2001 Apr;30(1):183-96
11343654
J Neurobiol. 2003 Feb 15;54(3):417-38
12532395
Curr Opin Neurobiol. 2009 Apr;19(2):168-73
19540746
J Neurophysiol. 2008 Aug;100(2):781-95
18579659
Pharmacol Ther. 2007 Mar;113(3):488-506
17240454
J Neurosci. 2010 Aug 11;30(32):10601-8
20702692
J Physiol. 2002 Oct 15;544(2):459-67
12381818
Nat Rev Neurosci. 2003 Jun;4(6):481-95
12778120
J Neurophysiol. 2009 Aug;102(2):1160-71
19494194
Naunyn Schmiedebergs Arch Pharmacol. 1988 Jun;337(6):687-9
3216901
Cell. 1994 Aug 26;78(4):535-8
8069904
J Neurosci. 1999 Mar 15;19(6):1932-9
10066246
J Neurophysiol. 2008 Oct;100(4):1897-908
18715900
J Neurosci. 2008 Sep 17;28(38):9557-63
18799687
J Physiol. 2004 May 15;557(Pt 1):3-12
15034124
J Neurophysiol. 2004 Jul;92(1):341-8
14973317
J Physiol. 2001 Dec 1;537(Pt 2):421-30
11731575
Trends Neurosci. 2007 Feb;30(2):54-61
17169441
J Neurosci. 2002 Feb 15;22(4):1248-55
11850452
Trends Neurosci. 1999 May;22(5):221-7
10322495
Brain Res. 1978 Jul 14;150(2):413-7
209851
Neuropharmacology. 1999 Oct;38(10):1431-76
10530808
J Physiol. 2003 Nov 15;553(Pt 1):155-67
12963794
Nat Neurosci. 1999 Jan;2(1):24-30
10195176
J Neurophysiol. 2003 Oct;90(4):2690-701
12815026
J Biol Chem. 1995 Jun 16;270(24):14340-6
7782293
Nature. 1999 Jul 29;400(6743):457-61
10440375
Neuron. 1997 Jun;18(6):969-82
9208864
Neuron. 1996 Jun;16(6):1229-36
8663999
Nat Neurosci. 2001 Oct;4(10):997-1005
11559854
Annu Rev Neurosci. 2001;24:31-55
11283304
Brain Res. 2000 Apr 28;863(1-2):271-5
10773218
Neuron. 1998 Oct;21(4):837-45
9808469
Neuron. 2001 Nov 20;32(4):697-709
11719209
Nature. 1983 Oct 20-26;305(5936):719-21
6415483
Trends Neurosci. 1997 Apr;20(4):170-7
9106358
Nature. 2006 Nov 2;444(7115):106-9
17065983
Nature. 2003 Aug 14;424(6950):775-8
12917685
Biochim Biophys Acta. 2007 Apr;1768(4):976-93
17078926
Neuron. 2002 Oct 24;36(3):475-82
12408849
Nat Rev Neurosci. 2004 Feb;5(2):97-107
14735113
J Neurophysiol. 1995 Jan;73(1):320-32
7714575
J Physiol. 1995 Oct 1;488 ( Pt 1):85-101
8568668
Physiol Rev. 2001 Jul;81(3):1065-96
11427692
Neurochem Int. 2000 Apr;36(4-5):291-300
10732996
J Neurosci. 2006 Jun 14;26(24):6618-26
16775150