title: Ephrin-A5 and EphA5 interaction induces synaptogenesis during early hippocampal development.
abstract: BACKGROUND
  Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.
  
  
  RESULTS
  Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.
  
  
  CONCLUSIONS
  These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation.
authors.affiliation: Department of Biochemistry, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Akaneya
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sohya
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kitamura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kimura
authors.forename: Chris
authors.initials: C
authors.lastname: Washburn
authors.forename: Renping
authors.initials: R
authors.lastname: Zhou
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
authors.forename: Tadaharu
authors.initials: T
authors.lastname: Tsumoto
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002450:Cell Communication; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D036386:Ephrin-A5 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D036123:Receptor, EphA5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D013131:Spine / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D036386:Ephrin-A5; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D036123:Receptor, EphA5; D017868:Cyclic AMP-Dependent Protein Kinases; D020764:cdc42 GTP-Binding Protein
references.citation: J Cell Sci. 2003 Jul 15;116(Pt 14):2823-32
references.pmid: 12808016
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7265-70
references.pmid: 17440041
references.citation: J Biol Chem. 2001 Jun 22;276(25):22100-6
references.pmid: 11285265
references.citation: Science. 2002 Jan 18;295(5554):491-5
references.pmid: 11799243
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H650-9
references.pmid: 15471984
references.citation: Pharmacol Ther. 1998 Mar;77(3):151-81
references.pmid: 9576626
references.citation: Neuron. 1998 Sep;21(3):581-91
references.pmid: 9768844
references.citation: Neuron. 2001 Sep 27;31(6):1001-13
references.pmid: 11580899
references.citation: J Neurosci. 1999 Aug 1;19(15):6528-37
references.pmid: 10414981
references.citation: Nature. 1984 Feb 2-8;307(5950):462-5
references.pmid: 6320006
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6418-23
references.pmid: 17404223
references.citation: Annu Rev Neurosci. 1999;22:511-39
references.pmid: 10202547
references.citation: Nature. 1991 Sep 19;353(6341):220
references.pmid: 1654522
references.citation: Annu Rev Neurosci. 1998;21:309-45
references.pmid: 9530499
references.citation: Oncogene. 1993 Dec;8(12):3277-88
references.pmid: 7504232
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:145-74
references.pmid: 11264454
references.citation: Neuron. 2003 Jan 23;37(2):263-74
references.pmid: 12546821
references.citation: Nat Neurosci. 2007 Jan;10(1):67-76
references.pmid: 17143272
references.citation: J Neurobiol. 1998 Oct;37(1):97-109
references.pmid: 9777735
references.citation: Prog Brain Res. 2008;169:97-115
references.pmid: 18394470
references.citation: Neuron. 2004 Apr 8;42(1):37-49
references.pmid: 15066263
references.citation: Mol Pharmacol. 2000 Nov;58(5):903-10
references.pmid: 11040036
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11024-31
references.pmid: 11572963
references.citation: J Cell Biol. 2003 Dec 22;163(6):1313-26
references.pmid: 14691139
references.citation: J Neurophysiol. 1992 Jul;68(1):55-69
references.pmid: 1517828
references.citation: Trends Neurosci. 1993 Sep;16(9):359-65
references.pmid: 7694406
references.citation: Cell. 2001 Apr 20;105(2):233-44
references.pmid: 11336673
references.citation: J Neurophysiol. 2001 Sep;86(3):1252-65
references.pmid: 11535674
references.citation: Brain Res Mol Brain Res. 1997 Jul;47(1-2):202-14
references.pmid: 9221918
references.citation: J Neurosci. 2009 Jun 24;29(25):8129-42
references.pmid: 19553453
references.citation: J Neurosci. 2003 Nov 26;23(34):10963-70
references.pmid: 14645492
references.citation: J Neurochem. 2004 Feb;88(3):564-75
references.pmid: 14720206
references.citation: Neuron. 2009 Feb 26;61(4):556-69
references.pmid: 19249276
references.citation: J Neurosci. 2000 Jan 1;20(1):266-73
references.pmid: 10627604
references.citation: Epilepsy Res. 1999 Sep;36(2-3):143-54
references.pmid: 10515162
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G812-9
references.pmid: 16782697
references.citation: J Neurosci. 2001 Jul 15;21(14):5079-88
references.pmid: 11438583
references.citation: J Comp Neurol. 2007 Apr 10;501(5):691-702
references.pmid: 17299751
references.citation: J Neurosci. 1999 Nov 1;19(21):9538-49
references.pmid: 10531456
references.citation: Nature. 1994 Mar 10;368(6467):144-7
references.pmid: 8139656
references.citation: Curr Opin Neurobiol. 2002 Jun;12(3):279-86
references.pmid: 12049934
references.citation: Neuroscience. 2005;135(2):451-61
references.pmid: 16112477
references.citation: J Neurophysiol. 2003 Nov;90(5):2964-72
references.pmid: 12867526
references.citation: Cell. 2000 Dec 8;103(6):945-56
references.pmid: 11136979
references.citation: Cell. 1995 Apr 7;81(1):53-62
references.pmid: 7536630
references.citation: J Biol Chem. 2006 Jan 20;281(3):1587-98
references.pmid: 16298995
references.citation: Curr Opin Neurobiol. 2001 Feb;11(1):118-26
references.pmid: 11179881
references.citation: Nature. 1984 May 17-23;309(5965):261-3
references.pmid: 6325946
references.citation: Neuron. 1990 Oct;5(4):501-9
references.pmid: 1688327
references.citation: Nat Rev Mol Cell Biol. 2002 Jul;3(7):475-86
references.pmid: 12094214
references.citation: Nat Neurosci. 1999 Jan;2(1):31-6
references.pmid: 10195177
references.citation: Experientia. 1990 Sep 15;46(9):882-91
references.pmid: 2209797
references.citation: Neuron. 1994 Jan;12(1):87-95
references.pmid: 8292362
references.citation: Nat Neurosci. 2004 May;7(5):501-9
references.pmid: 15107857
references.citation: J Physiol. 1991 Dec;444:25-49
references.pmid: 1822551
references.citation: J Neurosci. 2004 Mar 10;24(10):2542-50
references.pmid: 15014130
references.citation: Neuroscience. 1994 Nov;63(1):163-78
references.pmid: 7898646
references.citation: Curr Opin Neurobiol. 1998 Jun;8(3):364-9
references.pmid: 9687358
references.citation: Neuron. 2008 Jul 10;59(1):56-69
references.pmid: 18614029
references.citation: J Neurosci. 2005 Mar 16;25(11):2838-52
references.pmid: 15772344
references.citation: Ann N Y Acad Sci. 1995 Sep 7;766:442-58
references.pmid: 7486690
references.citation: Neuron. 2001 Dec 20;32(6):1027-40
references.pmid: 11754835
references.citation: Nat Neurosci. 2003 Feb;6(2):153-60
references.pmid: 12496762
references.citation: Trends Neurosci. 2002 Mar;25(3):145-9
references.pmid: 11852146
references.citation: Nature. 1997 Mar 20;386(6622):279-84
references.pmid: 9069286
references.citation: Mol Biol Cell. 2006 Mar;17(3):1273-85
references.pmid: 16394100
references.citation: Neuron. 2003 Jul 17;39(2):283-97
references.pmid: 12873385
references.citation: Curr Opin Neurobiol. 1997 Jun;7(3):419-29
references.pmid: 9232807
references.citation: J Neurosci. 2002 Sep 1;22(17):7548-57
references.pmid: 12196578
references.citation: Nat Rev Neurosci. 2001 Mar;2(3):155-64
references.pmid: 11256076
references.citation: Brain Res Mol Brain Res. 1995 May;30(1):1-16
references.pmid: 7609630
references.citation: Nat Neurosci. 2002 Nov;5(11):1117-8
references.pmid: 12389031
references.citation: Dev Biol. 2003 Nov 15;263(2):216-30
references.pmid: 14597197