title: Activation of α7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses.
abstract: Astrocytes, an abundant form of glia, are known to promote and modulate synaptic signaling between neurons. They also express α7-containing nicotinic acetylcholine receptors (α7-nAChRs), but the functional relevance of these receptors is unknown. We show here that stimulation of α7-nAChRs on astrocytes releases components that induce hippocampal neurons to acquire more α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors post-synaptically at glutamatergic synapses. The increase is specific in that no change is seen in synaptic NMDA receptor clusters or other markers for glutamatergic synapses, or in markers for GABAergic synapses. Moreover, the increases in AMPA receptors on the neuron surface are accompanied by increases in the frequency of spontaneous miniature synaptic currents mediated by the receptors and increases in the ratio of evoked synaptic currents mediated by AMPA versus NMDA receptors. This suggests that stimulating α7-nAChRs on astrocytes can convert 'silent' glutamatergic synapses to functional status. Astrocyte-derived thrombospondin is necessary but not sufficient for the effect, while tumor necrosis factor-α is sufficient but not necessary. The results identify astrocyte α7-nAChRs as a novel pathway through which nicotinic cholinergic signaling can promote the development of glutamatergic networks, recruiting AMPA receptors to post-synaptic sites and rendering the synapses more functional. We find that activation of nicotinic receptors on astrocytes releases a component that specifically recruits AMPA receptors to glutamatergic synapses. The recruitment appears to occur preferentially at what may be 'silent synapses', that is, synapses that have all the components required for glutamatergic transmission (including NMDA receptors) but lack sufficient AMPA receptors to generate a response. The results are unexpected and open up new possibilities for mechanisms underlying network formation and synaptic plasticity.
authors.affiliation: Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Xulong
authors.initials: X
authors.lastname: Wang
authors.forename: Giordano
authors.initials: G
authors.lastname: Lippi
authors.forename: David M
authors.initials: DM
authors.lastname: Carlson
authors.forename: Darwin K
authors.initials: DK
authors.lastname: Berg
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C579165:Chrna7 protein, rat; D018091:Receptors, AMPA; D064569:alpha7 Nicotinic Acetylcholine Receptor; D018698:Glutamic Acid
keywords: AMPA receptors; astrocytes; cholinergic; glutamatergic; nicotinic; synapse formation
references.citation: Glia. 2003 Jan 15;41(2):207-11
references.pmid: 12509811
references.citation: Curr Opin Neurobiol. 2010 Aug;20(4):466-73
references.pmid: 20471242
references.citation: Neuron. 2004 Sep 2;43(5):729-43
references.pmid: 15339653
references.citation: J Neurosci. 2009 Sep 23;29(38):11723-31
references.pmid: 19776259
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5190-5
references.pmid: 20212132
references.citation: J Neurosci Res. 2005 Feb 15;79(4):535-44
references.pmid: 15635597
references.citation: J Physiol. 2011 Jul 1;589(Pt 13):3333-48
references.pmid: 21558161
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6971-5
references.pmid: 7688468
references.citation: Neuron. 2009 Nov 12;64(3):391-403
references.pmid: 19914187
references.citation: Trends Pharmacol Sci. 2004 Jun;25(6):317-24
references.pmid: 15165747
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):E440-9
references.pmid: 21788491
references.citation: Science. 1995 Sep 22;269(5231):1692-6
references.pmid: 7569895
references.citation: Science. 2001 Nov 9;294(5545):1354-7
references.pmid: 11701931
references.citation: J Neurosci. 2011 Mar 16;31(11):4154-65
references.pmid: 21411656
references.citation: Dev Pharmacol Ther. 1985;8(6):384-95
references.pmid: 4075937
references.citation: Science. 2010 Nov 5;330(6005):790-6
references.pmid: 20929730
references.citation: J Physiol. 2006 Oct 15;576(Pt 2):533-46
references.pmid: 16901939
references.citation: J Neurosci. 2012 Jun 13;32(24):8391-400
references.pmid: 22699919
references.citation: J Neurochem. 2009 Feb;108(3):533-44
references.pmid: 19187090
references.citation: Nature. 2012 May 27;486(7403):410-4
references.pmid: 22722203
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:699-729
references.pmid: 17009926
references.citation: Nat Rev Neurosci. 2010 Apr;11(4):227-38
references.pmid: 20300101
references.citation: Nature. 2006 Apr 20;440(7087):1054-9
references.pmid: 16547515
references.citation: J Neurosci. 2008 Sep 10;28(37):9111-6
references.pmid: 18784291
references.citation: Nat Rev Neurosci. 2010 Jun;11(6):389-401
references.pmid: 20485364
references.citation: Physiol Rev. 2009 Jan;89(1):73-120
references.pmid: 19126755
references.citation: Mol Pharmacol. 2003 Feb;63(2):419-28
references.pmid: 12527814
references.citation: Science. 2006 Dec 8;314(5805):1610-3
references.pmid: 17158331
references.citation: J Neurosci. 2005 Mar 23;25(12):3219-28
references.pmid: 15788779
references.citation: Nat Neurosci. 2007 Mar;10(3):331-9
references.pmid: 17310248
references.citation: Nature. 2010 Jan 14;463(7278):232-6
references.pmid: 20075918
references.citation: Neuron. 2008 Nov 6;60(3):430-40
references.pmid: 18995817
references.citation: J Neurosci. 2010 Jun 30;30(26):8734-44
references.pmid: 20592195
references.citation: Mol Pharmacol. 2008 Aug;74(2):348-59
references.pmid: 18445710
references.citation: Science. 2010 Dec 17;330(6011):1677-81
references.pmid: 21164015
references.citation: Neuron. 2005 Apr 7;46(1):37-49
references.pmid: 15820692
references.citation: Neuron. 2011 Mar 10;69(5):988-1001
references.pmid: 21382557
references.citation: Neuron. 1995 Aug;15(2):427-34
references.pmid: 7646894
references.citation: Neuron. 2001 Dec 6;32(5):855-65
references.pmid: 11738031
references.citation: J Cell Biol. 1980 Jun;85(3):890-902
references.pmid: 6248568
references.citation: Neuropharmacology. 2009;56 Suppl 1:254-62
references.pmid: 18692078
references.citation: Cell. 2005 Feb 11;120(3):421-33
references.pmid: 15707899
references.citation: Glia. 2004 Aug 15;47(3):249-57
references.pmid: 15252814
references.citation: Science. 2005 Oct 7;310(5745):113-6
references.pmid: 16210541
references.citation: Hippocampus. 1995;5(6):605-20
references.pmid: 8646286
references.citation: Neurochem Int. 2005 Sep;47(4):281-90
references.pmid: 15955596
references.citation: Prog Neurobiol. 1997 Dec;53(5):603-25
references.pmid: 9421837
references.citation: Science. 2007 Aug 24;317(5841):1083-6
references.pmid: 17717185
references.citation: Cell. 2007 Dec 14;131(6):1164-78
references.pmid: 18083105
references.citation: Nature. 1996 Oct 24;383(6602):713-6
references.pmid: 8878480
references.citation: Cell. 2009 Oct 16;139(2):380-92
references.pmid: 19818485
references.citation: J Neurosci. 2012 May 30;32(22):7651-61
references.pmid: 22649244
references.citation: Nat Rev Neurosci. 2013 May;14(5):311-21
references.pmid: 23595014
references.citation: J Neurosci. 2006 Dec 6;26(49):12769-80
references.pmid: 17151280
references.citation: Nature. 1995 Jun 1;375(6530):400-4
references.pmid: 7760933
references.citation: J Physiol. 2007 Mar 15;579(Pt 3):753-63
references.pmid: 17204496
references.citation: Nan Fang Yi Ke Da Xue Xue Bao. 2007 May;27(5):591-4
references.pmid: 17545063
references.citation: Annu Rev Physiol. 2001;63:795-813
references.pmid: 11181976
references.citation: Nat Rev Neurosci. 2004 Jan;5(1):55-65
references.pmid: 14708004
references.citation: Science. 2002 Mar 22;295(5563):2282-5
references.pmid: 11910117
references.citation: Curr Neuropharmacol. 2007 Sep;5(3):213-22
references.pmid: 19305804
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Mol Cell Neurosci. 2006 Dec;33(4):381-8
references.pmid: 17029981
references.citation: Neuron. 2011 Jul 14;71(1):155-65
references.pmid: 21745645
references.citation: Trends Neurosci. 2003 Oct;26(10):536-42
references.pmid: 14522146
references.citation: Nature. 2010 Nov 11;468(7321):223-31
references.pmid: 21068831
references.citation: J Neurosci. 2001 Mar 1;21(5):1452-63
references.pmid: 11222635
references.citation: J Cell Biol. 2011 Sep 19;194(6):889-904
references.pmid: 21930776
references.citation: J Neurosci. 2003 Jan 15;23(2):587-600
references.pmid: 12533619
references.citation: Int J Dev Neurosci. 1998 Oct;16(6):507-18
references.pmid: 9881299
references.citation: Mol Cell Neurosci. 2002 Dec;21(4):616-25
references.pmid: 12504594
references.citation: J Neurophysiol. 2011 Dec;106(6):2876-87
references.pmid: 21900512
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4148-53
references.pmid: 11259680
references.citation: J Neurosci. 2000 Oct 15;20(20):7672-81
references.pmid: 11027228
references.citation: Brain Res Dev Brain Res. 2002 Dec 15;139(2):175-87
references.pmid: 12480132
references.citation: J Neurosci. 1993 Feb;13(2):596-604
references.pmid: 7678857
references.citation: Biochem Pharmacol. 2009 Oct 1;78(7):703-11
references.pmid: 19481063
references.citation: Cell. 2011 Sep 2;146(5):785-98
references.pmid: 21855979