Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons.
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.
Lin
Hong
H
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Vicini
Stefano
S
Hsu
Fu-Chun
FC
Doshi
Shachee
S
Takano
Hajime
H
Coulter
Douglas A
DA
Lynch
David R
DR
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
C579165:Chrna7 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor
J Neurosci. 1998 Oct 15;18(20):8485-95
9763491
Trends Neurosci. 2006 Jun;29(6):323-9
16697057
Neuropharmacology. 2006 Feb;50(2):254-68
16324726
J Neurochem. 2009 Sep;110(5):1598-606
19723266
J Neurophysiol. 2002 Dec;88(6):3315-30
12466449
CNS Drugs. 2008;22(9):705-24
18698872
Curr Opin Neurobiol. 2007 Oct;17(5):516-24
17950593
Brain Res. 1995 Mar 20;674(2):252-9
7796104
Neurobiol Learn Mem. 2003 Nov;80(3):285-90
14521870
Genes Brain Behav. 2006 Aug;5(6):433-40
16923147
J Neurosci. 2007 Sep 12;27(37):9835-45
17855598
J Pharmacol Exp Ther. 2009 Feb;328(2):364-70
19023041
J Neurosci. 2005 Jun 29;25(26):6084-91
15987938
J Neurobiol. 2002 Dec;53(4):457-78
12436413
J Alzheimers Dis. 2010;19(1):69-77
20061627
Annu Rev Pharmacol Toxicol. 2007;47:699-729
17009926
Neuron. 2006 Mar 16;49(6):877-87
16543135
J Neurosci. 2008 Sep 10;28(37):9111-6
18784291
Neuroscientist. 2005 Feb;11(1):37-49
15632277
Biochem Pharmacol. 2009 Oct 1;78(7):686-92
19464268
Neuropharmacology. 2009 May-Jun;56(6-7):1001-9
19233218
Neuropharmacology. 2000 Oct;39(13):2799-807
11044750
Neurosci Lett. 2000 Jun 2;286(2):134-8
10825655
Pharmacol Rev. 1999 Mar;51(1):7-61
10049997
J Cell Biol. 2008 May 5;181(3):511-21
18458158
Biol Cell. 2004 May;96(4):257-60
15145529
J Neurosci. 2009 Jul 8;29(27):8805-15
19587288
Learn Mem. 2008 Aug 06;15(8):603-10
18685152
Neuropharmacology. 2000 Oct;39(13):2715-25
11044742
Prog Brain Res. 2005;148:307-20
15661199
J Neurosci. 2010 Feb 17;30(7):2442-53
20164328
J Neurophysiol. 2008 Dec;100(6):3175-84
18922945
J Neurosci. 2006 Oct 18;26(42):10813-25
17050720
J Neurosci. 2006 Oct 4;26(40):10199-208
17021175
Pharmacol Ther. 2009 Jun;122(3):302-11
19351547
Neuron. 2006 Mar 16;49(6):861-75
16543134
J Neurosci. 2004 Dec 15;24(50):11244-52
15601930
Eur J Neurosci. 1998 May;10(5):1553-62
9751128
Brain Res. 2009 Sep 29;1291:1-11
19631623
Neuroscientist. 2008 Dec;14(6):609-25
19029059
J Neurochem. 2003 Mar;84(5):952-9
12603820
Curr Pharm Des. 2010;16(5):538-54
19909231
J Mol Neurosci. 2006;30(1-2):181-4
17192671
Cell. 2004 Mar 19;116(6):869-81
15035988
Eur J Neurosci. 2006 Apr;23(7):1819-28
16623839
J Neurosci Res. 2001 Nov 15;66(4):565-72
11746376
Eur J Neurosci. 2006 Dec;24(11):3271-84
17156388
J Neurosci. 2007 Sep 26;27(39):10508-19
17898222
Brain Res. 2006 Feb 9;1072(1):72-8
16406013
Neuromolecular Med. 2008;10(4):377-84
18696274
J Neurosci. 2005 Feb 23;25(8):2024-31
15728842
Neuroscience. 2010 Apr 28;167(1):68-87
20096331