title: Molecular mechanisms determining conserved properties of short-term synaptic depression revealed in NSF and SNAP-25 conditional mutants.
abstract: Current models of synaptic vesicle trafficking implicate a core complex of proteins comprised of N-ethylmaleimide-sensitive factor (NSF), soluble NSF attachment proteins (SNAPs), and SNAREs in synaptic vesicle fusion and neurotransmitter release. Despite this progress, major challenges remain in establishing the in vivo functions of these proteins and their roles in determining the physiological properties of synapses. The present study employs glutamatergic adult neuromuscular synapses of Drosophila, which exhibit conserved properties of short-term synaptic plasticity with respect to mammalian glutamatergic synapses, to address these issues through genetic analysis. Our findings establish an in vivo role for SNAP-25 in synaptic vesicle priming, and support a zippering model of SNARE function in this process. Moreover, these studies define the contribution of SNAP-25-dependent vesicle priming to the detailed properties of short-term depression elicited by paired-pulse (PP) and train stimulation. In contrast, NSF is shown here not to be required for WT PP depression, but to be critical for maintaining neurotransmitter release during sustained stimulation. In keeping with this role, disruption of NSF function results in activity-dependent redistribution of the t-SNARE proteins, SYNTAXIN and SNAP-25, away from neurotransmitter release sites (active zones). These findings support a role for NSF in replenishing active zone t-SNAREs for subsequent vesicle priming, and provide new insight into the spatial organization of SNARE protein cycling during synaptic activity. Together, the results reported here establish in vivo contributions of SNAP-25 and NSF to synaptic vesicle trafficking and define molecular mechanisms determining conserved functional properties of short-term depression.
authors.affiliation: Department of Biology and Center for Molecular and Cellular Neuroscience, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kawasaki
authors.forename: Richard W
authors.initials: RW
authors.lastname: Ordway
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004594:Electrophysiology; D005071:Evoked Potentials / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D007150:Immunohistochemistry; D009154:Mutation; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D029721:Drosophila Proteins; D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; C494207:Snap25 protein, Drosophila; D050825:Synaptosomal-Associated Protein 25; C498732:comt protein, Drosophila; D052066:N-Ethylmaleimide-Sensitive Proteins
references.citation: Neuron. 2004 Jul 8;43(1):119-31
references.pmid: 15233922
references.citation: J Neurobiol. 1983 May;14(3):207-25
references.pmid: 6304244
references.citation: Neuroscience. 2008 Jun 2;153(4):1048-63
references.pmid: 18436388
references.citation: Nat Rev Neurosci. 2002 Aug;3(8):641-53
references.pmid: 12154365
references.citation: Nat Neurosci. 2002 Jan;5(1):19-26
references.pmid: 11753414
references.citation: Mol Membr Biol. 2003 Jul-Sep;20(3):209-20
references.pmid: 12893529
references.citation: Neuron. 2001 Dec 20;32(6):1119-31
references.pmid: 11754842
references.citation: J Physiol. 1970 Mar;206(3):629-44
references.pmid: 5498509
references.citation: J Comp Neurol. 1988 Jul 15;273(3):436-44
references.pmid: 3145293
references.citation: Genetics. 2003 May;164(1):163-71
references.pmid: 12750329
references.citation: EMBO J. 2006 Mar 8;25(5):955-66
references.pmid: 16498411
references.citation: J Neurophysiol. 1999 Apr;81(4):1495-505
references.pmid: 10200186
references.citation: EMBO J. 2001 Dec 3;20(23):6761-71
references.pmid: 11726512
references.citation: Trends Neurosci. 2002 Apr;25(4):206-12
references.pmid: 11998689
references.citation: Neuron. 2008 Sep 25;59(6):861-72
references.pmid: 18817727
references.citation: Nature. 2000 Aug 24;406(6798):849-54
references.pmid: 10972279
references.citation: J Neurosci. 2007 Aug 29;27(35):9380-91
references.pmid: 17728451
references.citation: Neuron. 1997 Jun;18(6):995-1008
references.pmid: 9208866
references.citation: J Neurosci. 1998 Dec 15;18(24):10241-9
references.pmid: 9852561
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5715-9
references.pmid: 8202553
references.citation: Nature. 1995 Jul 6;376(6535):25
references.pmid: 7596428
references.citation: J Biol Chem. 1995 Aug 11;270(32):18742-4
references.pmid: 7642522
references.citation: Neuron. 1999 Aug;23(4):821-32
references.pmid: 10482247
references.citation: J Neurosci. 2007 Dec 26;27(52):14286-98
references.pmid: 18160636
references.citation: J Neurosci. 1998 Dec 15;18(24):10250-6
references.pmid: 9852562
references.citation: Proc Natl Acad Sci U S A. 1976 Sep;73(9):3253-7
references.pmid: 184469
references.citation: J Neurosci. 2007 Mar 21;27(12):3198-210
references.pmid: 17376981
references.citation: Annu Rev Physiol. 2002;64:355-405
references.pmid: 11826273
references.citation: J Neurosci. 1998 Aug 15;18(16):6147-62
references.pmid: 9698309
references.citation: Methods Cell Biol. 2003;71:195-265
references.pmid: 12884693
references.citation: Nature. 1998 Jul 23;394(6691):384-8
references.pmid: 9690475
references.citation: J Neurophysiol. 1999 Jul;82(1):123-30
references.pmid: 10400941
references.citation: J Neurosci. 2000 Jul 1;20(13):4885-9
references.pmid: 10864946
references.citation: J Neurophysiol. 2005 May;93(5):2396-405
references.pmid: 15845998
references.citation: Neuron. 2003 Jul 31;39(3):529-41
references.pmid: 12895425
references.citation: J Neurophysiol. 1995 Aug;74(2):529-38
references.pmid: 7472360
references.citation: J Cell Biol. 2000 Oct 16;151(2):439-52
references.pmid: 11038189
references.citation: Curr Opin Neurobiol. 1997 Jun;7(3):310-5
references.pmid: 9232812
references.citation: Neuron. 1998 Aug;21(2):415-24
references.pmid: 9728922
references.citation: Biophys J. 1999 Nov;77(5):2418-29
references.pmid: 10545345
references.citation: Nat Neurosci. 2000 Sep;3(9):859-60
references.pmid: 10966613
references.citation: J Neurosci. 2004 Jan 7;24(1):282-5
references.pmid: 14715960
references.citation: J Neurosci. 2003 Jan 15;23(2):377-83
references.pmid: 12533597
references.citation: J Neurosci. 2002 Jul 15;22(14):5856-64
references.pmid: 12122048
references.citation: Nature. 1993 Mar 25;362(6418):318-24
references.pmid: 8455717
references.citation: J Neurobiol. 2004 Sep 15;60(4):499-516
references.pmid: 15307154
references.citation: Nat Neurosci. 1999 Dec;2(12):1078-83
references.pmid: 10570484
references.citation: Neuron. 2007 Feb 15;53(4):563-75
references.pmid: 17296557
references.citation: Nat Rev Neurosci. 2005 Jan;6(1):57-69
references.pmid: 15611727
references.citation: Neuron. 2002 Dec 19;36(6):1115-26
references.pmid: 12495626
references.citation: Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7095-9
references.pmid: 7624376
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):347-52
references.pmid: 18172208
references.citation: Neuron. 1999 Jun;23(2):399-409
references.pmid: 10399944