title: Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons.
abstract: In association with NMDA receptors (NMDARs), neuronal α7 nicotinic ACh receptors (nAChRs) have been implicated in neuronal plasticity as well as neurodevelopmental, neurological, and psychiatric disorders. However, the role of presynaptic NMDARs and their interaction with α7 nAChRs in these physiological and pathophysiological events remains unknown. Here we report that axonal α7 nAChRs modulate presynaptic NMDAR expression and structural plasticity of glutamatergic presynaptic boutons during early synaptic development. Chronic inactivation of α7 nAChRs markedly increased cell surface NMDAR expression as well as the number and size of glutamatergic axonal varicosities in cortical cultures. These boutons contained presynaptic NMDARs and α7 nAChRs, and recordings from outside-out pulled patches of enlarged presynaptic boutons identified functional NMDAR-mediated currents. Multiphoton imaging of presynaptic NMDAR-mediated calcium transients demonstrated significantly larger responses in these enlarged boutons, suggesting enhanced presynaptic NMDAR function that could lead to increased glutamate release. Moreover, whole-cell patch clamp showed a significant increase in synaptic charge mediated by NMDAR miniature EPSCs but no alteration in the frequency of AMPAR miniature EPSCs, suggesting the selective enhancement of postsynaptically silent synapses upon inactivation of α7 nAChRs. Taken together, these findings indicate that axonal α7 nAChRs modulate presynaptic NMDAR expression and presynaptic and postsynaptic maturation of glutamatergic synapses, and implicate presynaptic α7 nAChR/NMDAR interactions in synaptic development and plasticity.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicini
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Hsu
authors.forename: Shachee
authors.initials: S
authors.lastname: Doshi
authors.forename: Hajime
authors.initials: H
authors.lastname: Takano
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Coulter
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D020013:Calcium Signaling; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D055369:Miniature Postsynaptic Potentials; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor
references.citation: J Neurosci. 1998 Oct 15;18(20):8485-95
references.pmid: 9763491
references.citation: Trends Neurosci. 2006 Jun;29(6):323-9
references.pmid: 16697057
references.citation: Neuropharmacology. 2006 Feb;50(2):254-68
references.pmid: 16324726
references.citation: J Neurochem. 2009 Sep;110(5):1598-606
references.pmid: 19723266
references.citation: J Neurophysiol. 2002 Dec;88(6):3315-30
references.pmid: 12466449
references.citation: CNS Drugs. 2008;22(9):705-24
references.pmid: 18698872
references.citation: Curr Opin Neurobiol. 2007 Oct;17(5):516-24
references.pmid: 17950593
references.citation: Brain Res. 1995 Mar 20;674(2):252-9
references.pmid: 7796104
references.citation: Neurobiol Learn Mem. 2003 Nov;80(3):285-90
references.pmid: 14521870
references.citation: Genes Brain Behav. 2006 Aug;5(6):433-40
references.pmid: 16923147
references.citation: J Neurosci. 2007 Sep 12;27(37):9835-45
references.pmid: 17855598
references.citation: J Pharmacol Exp Ther. 2009 Feb;328(2):364-70
references.pmid: 19023041
references.citation: J Neurosci. 2005 Jun 29;25(26):6084-91
references.pmid: 15987938
references.citation: J Neurobiol. 2002 Dec;53(4):457-78
references.pmid: 12436413
references.citation: J Alzheimers Dis. 2010;19(1):69-77
references.pmid: 20061627
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:699-729
references.pmid: 17009926
references.citation: Neuron. 2006 Mar 16;49(6):877-87
references.pmid: 16543135
references.citation: J Neurosci. 2008 Sep 10;28(37):9111-6
references.pmid: 18784291
references.citation: Neuroscientist. 2005 Feb;11(1):37-49
references.pmid: 15632277
references.citation: Biochem Pharmacol. 2009 Oct 1;78(7):686-92
references.pmid: 19464268
references.citation: Neuropharmacology. 2009 May-Jun;56(6-7):1001-9
references.pmid: 19233218
references.citation: Neuropharmacology. 2000 Oct;39(13):2799-807
references.pmid: 11044750
references.citation: Neurosci Lett. 2000 Jun 2;286(2):134-8
references.pmid: 10825655
references.citation: Pharmacol Rev. 1999 Mar;51(1):7-61
references.pmid: 10049997
references.citation: J Cell Biol. 2008 May 5;181(3):511-21
references.pmid: 18458158
references.citation: Biol Cell. 2004 May;96(4):257-60
references.pmid: 15145529
references.citation: J Neurosci. 2009 Jul 8;29(27):8805-15
references.pmid: 19587288
references.citation: Learn Mem. 2008 Aug 06;15(8):603-10
references.pmid: 18685152
references.citation: Neuropharmacology. 2000 Oct;39(13):2715-25
references.pmid: 11044742
references.citation: Prog Brain Res. 2005;148:307-20
references.pmid: 15661199
references.citation: J Neurosci. 2010 Feb 17;30(7):2442-53
references.pmid: 20164328
references.citation: J Neurophysiol. 2008 Dec;100(6):3175-84
references.pmid: 18922945
references.citation: J Neurosci. 2006 Oct 18;26(42):10813-25
references.pmid: 17050720
references.citation: J Neurosci. 2006 Oct 4;26(40):10199-208
references.pmid: 17021175
references.citation: Pharmacol Ther. 2009 Jun;122(3):302-11
references.pmid: 19351547
references.citation: Neuron. 2006 Mar 16;49(6):861-75
references.pmid: 16543134
references.citation: J Neurosci. 2004 Dec 15;24(50):11244-52
references.pmid: 15601930
references.citation: Eur J Neurosci. 1998 May;10(5):1553-62
references.pmid: 9751128
references.citation: Brain Res. 2009 Sep 29;1291:1-11
references.pmid: 19631623
references.citation: Neuroscientist. 2008 Dec;14(6):609-25
references.pmid: 19029059
references.citation: J Neurochem. 2003 Mar;84(5):952-9
references.pmid: 12603820
references.citation: Curr Pharm Des. 2010;16(5):538-54
references.pmid: 19909231
references.citation: J Mol Neurosci. 2006;30(1-2):181-4
references.pmid: 17192671
references.citation: Cell. 2004 Mar 19;116(6):869-81
references.pmid: 15035988
references.citation: Eur J Neurosci. 2006 Apr;23(7):1819-28
references.pmid: 16623839
references.citation: J Neurosci Res. 2001 Nov 15;66(4):565-72
references.pmid: 11746376
references.citation: Eur J Neurosci. 2006 Dec;24(11):3271-84
references.pmid: 17156388
references.citation: J Neurosci. 2007 Sep 26;27(39):10508-19
references.pmid: 17898222
references.citation: Brain Res. 2006 Feb 9;1072(1):72-8
references.pmid: 16406013
references.citation: Neuromolecular Med. 2008;10(4):377-84
references.pmid: 18696274
references.citation: J Neurosci. 2005 Feb 23;25(8):2024-31
references.pmid: 15728842
references.citation: Neuroscience. 2010 Apr 28;167(1):68-87
references.pmid: 20096331