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PMID: 17090216 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Rapid redistribution of synaptic PSD-95 in the neocortex in vivo.

PLoS biology ·Vol. 4 ·No. 11 ·2006-11-00 ·Pages e370

Gray NW, Weimer RM, Bureau I, Svoboda K

Abstract

Most excitatory synapses terminate on dendritic spines. Spines vary in size, and their volumes are proportional to the area of the postsynaptic density (PSD) and synaptic strength. PSD-95 is an abundant multi-domain postsynaptic scaffolding protein that clusters glutamate receptors and organizes the associated signaling complexes. PSD-95 is thought to determine the size and strength of synapses. Although spines and their synapses can persist for months in vivo, PSD-95 and other PSD proteins have shorter half-lives in vitro, on the order of hours. To probe the mechanisms underlying synapse stability, we measured the dynamics of synaptic PSD-95 clusters in vivo. Using two-photon microscopy, we imaged PSD-95 tagged with GFP in layer 2/3 dendrites in the developing (postnatal day 10-21) barrel cortex. A subset of PSD-95 clusters was stable for days. Using two-photon photoactivation of PSD-95 tagged with photoactivatable GFP (paGFP), we measured the time over which PSD-95 molecules were retained in individual spines. Synaptic PSD-95 turned over rapidly (median retention times tau(r) is approximately 22-63 min from P10-P21) and exchanged with PSD-95 in neighboring spines by diffusion. PSDs therefore share a dynamic pool of PSD-95. Large PSDs in large spines captured more diffusing PSD-95 and also retained PSD-95 longer than small PSDs. Changes in the sizes of individual PSDs over days were associated with concomitant changes in PSD-95 retention times. Furthermore, retention times increased with developmental age (tau(r) is approximately 100 min at postnatal day 70) and decreased dramatically following sensory deprivation. Our data suggest that individual PSDs compete for PSD-95 and that the kinetic interactions between PSD molecules and PSDs are tuned to regulate PSD size.

MeSH Terms
Animals Disks Large Homolog 4 Protein Embryo, Mammalian/surgery Female Guanylate Kinases Intracellular Signaling Peptides and Proteins/metabolism Membrane Proteins/metabolism Mice Mice, Inbred C57BL Models, Biological Models, Neurological Neocortex/metabolism Nerve Tissue Proteins/metabolism Neurons, Afferent/metabolism Pregnancy Protein Binding Synapses/metabolism Time Factors Tissue Distribution
Chemicals
Disks Large Homolog 4 Protein Dlg4 protein, mouse Intracellular Signaling Peptides and Proteins Membrane Proteins Nerve Tissue Proteins postsynaptic density proteins Guanylate Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Gray Noah W
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Weimer Robby M
Bureau Ingrid
Svoboda Karel
Conflict of Interest

Competing interests. The authors have declared that no competing interests exist.

References (82)
82 references, click to expand
  1. Modulation of spike timing by sensory deprivation during induction of cortical map plasticity.
    Nat Neurosci. 2004 May;7(5):534-41 PMID: 15064767
  2. Precise development of functional and anatomical columns in the neocortex.
    Neuron. 2004 Jun 10;42(5):789-801 PMID: 15182718
  3. ScanImage: flexible software for operating laser scanning microscopes.
    Biomed Eng Online. 2003 May 17;2:13 PMID: 12801419
  4. PDZ domain proteins of synapses.
    Nat Rev Neurosci. 2004 Oct;5(10):771-81 PMID: 15378037
  5. A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis.
    Neuropharmacology. 2004 Oct;47(5):755-63 PMID: 15458847
  6. Induction of spine growth and synapse formation by regulation of the spine actin cytoskeleton.
    Neuron. 2004 Oct 14;44(2):321-34 PMID: 15473970
  7. Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions.
    Neuron. 2004 Oct 28;44(3):453-67 PMID: 15504326
  8. Maturation of pyramidal cell form in relation to developing afferent and efferent connections of rat somatic sensory cortex.
    Neuroscience. 1979;4(9):1275-97 PMID: 492537
  9. A laminar analysis of the number of round-asymmetrical and flat-symmetrical synapses on spines, dendritic trunks, and cell bodies in area 17 of the cat.
    J Comp Neurol. 1985 Jan 8;231(2):180-9 PMID: 3968234
  10. Changes in the subcellular distribution of calmodulin-kinase II during brain development.
    Brain Res. 1985 Feb;350(1-2):211-24 PMID: 3986614
  11. Two developmentally regulated isoenzymes of calmodulin-stimulated protein kinase II in rat forebrain.
    J Neurochem. 1988 Mar;50(3):945-53 PMID: 2828551
  12. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics.
    J Neurosci. 1989 Aug;9(8):2982-97 PMID: 2769375
  13. Two-photon laser scanning fluorescence microscopy.
    Science. 1990 Apr 6;248(4951):73-6 PMID: 2321027
  14. Efficient selection for high-expression transfectants with a novel eukaryotic vector.
    Gene. 1991 Dec 15;108(2):193-9 PMID: 1660837
  15. Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases.
    J Neurosci. 1996 Apr 1;16(7):2157-63 PMID: 8601796
  16. Direct measurement of coupling between dendritic spines and shafts.
    Science. 1996 May 3;272(5262):716-9 PMID: 8614831
  17. Quantitative aspects of synaptogenesis in the rat barrel field cortex with special reference to GABA circuitry.
    J Comp Neurol. 1996 Sep 23;373(3):340-54 PMID: 8889932
  18. Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage.
    Cell. 1997 Dec 26;91(7):927-38 PMID: 9428516
  19. Differential expression of isoforms of PSD-95 binding protein (GKAP/SAPAP1) during rat brain development.
    FEBS Lett. 1997 Dec 1;418(3):301-4 PMID: 9428732
  20. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons.
    Nat Neurosci. 2001 Nov;4(11):1086-92 PMID: 11687814
  21. Rapid redistribution of the postsynaptic density protein PSD-Zip45 (Homer 1c) and its differential regulation by NMDA receptors and calcium channels.
    J Neurosci. 2001 Dec 15;21(24):9561-71 PMID: 11739567
  22. Efficient gene transfer into the embryonic mouse brain using in vivo electroporation.
    Dev Biol. 2001 Dec 1;240(1):237-46 PMID: 11784059
  23. Structure and function of dendritic spines.
    Annu Rev Physiol. 2002;64:313-53 PMID: 11826272
  24. Rapid turnover of actin in dendritic spines and its regulation by activity.
    Nat Neurosci. 2002 Mar;5(3):239-46 PMID: 11850630
  25. Synaptic strength regulated by palmitate cycling on PSD-95.
    Cell. 2002 Mar 22;108(6):849-63 PMID: 11955437
  26. Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells.
    Science. 2002 May 3;296(5569):913-6 PMID: 11988576
  27. Adenoviral-mediated, high-level, cell-specific transgene expression: a SYN1-WPRE cassette mediates increased transgene expression with no loss of neuron specificity.
    Mol Ther. 2002 May;5(5 Pt 1):509-16 PMID: 11991741
  28. The molecular basis of CaMKII function in synaptic and behavioural memory.
    Nat Rev Neurosci. 2002 Mar;3(3):175-90 PMID: 11994750
  29. A photoactivatable GFP for selective photolabeling of proteins and cells.
    Science. 2002 Sep 13;297(5588):1873-7 PMID: 12228718
  30. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number.
    Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13902-7 PMID: 12359873
  31. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex.
    Nature. 2002 Dec 19-26;420(6917):788-94 PMID: 12490942
  32. Long-term dendritic spine stability in the adult cortex.
    Nature. 2002 Dec 19-26;420(6917):812-6 PMID: 12490949
  33. Molecular mechanisms of glutamate receptor clustering at excitatory synapses.
    Curr Opin Neurobiol. 1998 Jun;8(3):364-9 PMID: 9687358
  34. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus.
    Neuron. 1998 Sep;21(3):545-59 PMID: 9768841
  35. Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation.
    Science. 1999 Apr 2;284(5411):162-6 PMID: 10102820
  36. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation.
    Science. 1999 Jun 11;284(5421):1811-6 PMID: 10364548
  37. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses.
    Nat Neurosci. 1999 Jul;2(7):618-24 PMID: 10409387
  38. Continual remodeling of postsynaptic density and its regulation by synaptic activity.
    Nat Neurosci. 1999 Sep;2(9):804-11 PMID: 10461219
  39. Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development.
    J Biol Chem. 1999 Oct 8;274(41):29510-8 PMID: 10506216
  40. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein.
    Nat Biotechnol. 2004 Dec;22(12):1567-72 PMID: 15558047
  41. Competing for memory: hippocampal LTP under regimes of reduced protein synthesis.
    Neuron. 2004 Dec 16;44(6):1011-20 PMID: 15603743
  42. Transient and persistent dendritic spines in the neocortex in vivo.
    Neuron. 2005 Jan 20;45(2):279-91 PMID: 15664179
  43. Development of long-term dendritic spine stability in diverse regions of cerebral cortex.
    Neuron. 2005 Apr 21;46(2):181-9 PMID: 15848798
  44. Diverse modes of axon elaboration in the developing neocortex.
    PLoS Biol. 2005 Aug;3(8):e272 PMID: 16026180
  45. Mass of the postsynaptic density and enumeration of three key molecules.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11551-6 PMID: 16061821
  46. Determination of absolute protein numbers in single synapses by a GFP-based calibration technique.
    Nat Methods. 2005 Sep;2(9):677-84 PMID: 16118638
  47. Clusters of interacting receptors can stabilize synaptic efficacies.
    Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14440-5 PMID: 16189022
  48. Neuronal activity regulates diffusion across the neck of dendritic spines.
    Science. 2005 Nov 4;310(5749):866-9 PMID: 16272125
  49. Essential contribution of the ligand-binding beta B/beta C loop of PDZ1 and PDZ2 in the regulation of postsynaptic clustering, scaffolding, and localization of postsynaptic density-95.
    J Neurosci. 2006 Jan 18;26(3):763-74 PMID: 16421296
  50. Molecular mechanisms of dendritic spine morphogenesis.
    Curr Opin Neurobiol. 2006 Feb;16(1):95-101 PMID: 16361095
  51. Auxiliary subunits assist AMPA-type glutamate receptors.
    Science. 2006 Mar 3;311(5765):1253-6 PMID: 16513974
  52. Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP.
    Neuron. 2001 Aug 2;31(2):289-303 PMID: 11502259
  53. Rapid development and plasticity of layer 2/3 maps in rat barrel cortex in vivo.
    Neuron. 2001 Aug 2;31(2):305-15 PMID: 11502260
  54. Rapid formation and remodeling of postsynaptic densities in developing dendrites.
    Nat Neurosci. 2001 Oct;4(10):1006-13 PMID: 11574832
  55. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system.
    Nat Neurosci. 2003 Mar;6(3):231-42 PMID: 12577062
  56. Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks.
    J Cell Sci. 2003 Aug 1;116(Pt 15):3213-9 PMID: 12829740
  57. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression.
    J Neurosci. 2003 Jul 2;23(13):5503-6 PMID: 12843250
  58. Remodeling of synaptic structure in sensory cortical areas in vivo.
    J Neurosci. 2006 Mar 15;26(11):3021-9 PMID: 16540580
  59. Postsynaptic protein mobility in dendritic spines: long-term regulation by synaptic NMDA receptor activation.
    Mol Cell Neurosci. 2006 Apr;31(4):702-12 PMID: 16504537
  60. Principles of two-photon excitation microscopy and its applications to neuroscience.
    Neuron. 2006 Jun 15;50(6):823-39 PMID: 16772166
  61. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum.
    Mol Cell Proteomics. 2006 Jun;5(6):1158-70 PMID: 16507876
  62. Experience-dependent and cell-type-specific spine growth in the neocortex.
    Nature. 2006 Jun 22;441(7096):979-83 PMID: 16791195
  63. Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function.
    Neuron. 2006 Jul 6;51(1):99-111 PMID: 16815335
  64. Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms.
    J Neurosci. 2006 Jul 19;26(29):7693-706 PMID: 16855097
  65. Spine growth precedes synapse formation in the adult neocortex in vivo.
    Nat Neurosci. 2006 Sep;9(9):1117-24 PMID: 16892056
  66. Development of neuron-neuron synapses.
    Curr Opin Neurobiol. 2000 Feb;10(1):125-31 PMID: 10679427
  67. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo.
    Nature. 2000 Apr 20;404(6780):876-81 PMID: 10786794
  68. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.
    Nat Neurosci. 2000 Jul;3(7):661-9 PMID: 10862698
  69. Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment.
    Neuron. 2000 Jul;27(1):57-69 PMID: 10939331
  70. Actin-dependent regulation of neurotransmitter release at central synapses.
    Neuron. 2000 Sep;27(3):539-50 PMID: 11055436
  71. PSD-95 involvement in maturation of excitatory synapses.
    Science. 2000 Nov 17;290(5495):1364-8 PMID: 11082065
  72. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.
    Nature. 2000 Dec 21-28;408(6815):936-43 PMID: 11140673
  73. Efficient in utero gene transfer system to the developing mouse brain using electroporation: visualization of neuronal migration in the developing cortex.
    Neuroscience. 2001;103(4):865-72 PMID: 11301197
  74. Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex.
    Synapse. 2001 Jun 15;40(4):239-57 PMID: 11309840
  75. Regulation of dendritic spine morphology and synaptic function by Shank and Homer.
    Neuron. 2001 Jul 19;31(1):115-30 PMID: 11498055
  76. Compartmentalized synthesis and degradation of proteins in neurons.
    Neuron. 2003 Oct 9;40(2):347-59 PMID: 14556713
  77. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.
    Neuron. 2003 Oct 30;40(3):595-607 PMID: 14642282
  78. Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD.
    J Neurosci. 2003 Dec 3;23(35):11270-8 PMID: 14657186
  79. Genesis of dendritic spines: insights from ultrastructural and imaging studies.
    Nat Rev Neurosci. 2004 Jan;5(1):24-34 PMID: 14708001
  80. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity.
    J Neurosci. 2004 Jan 28;24(4):916-27 PMID: 14749436
  81. Postsynaptic density assembly is fundamentally different from presynaptic active zone assembly.
    J Neurosci. 2004 Feb 11;24(6):1507-20 PMID: 14960624
  82. In vivo imaging of synapse formation on a growing dendritic arbor.
    Nat Neurosci. 2004 Mar;7(3):254-60 PMID: 14758365
Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.0040370
Published
2006-11-00
Pages
e370
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC1634879
Subset
IM
Corrections
CommentIn
PMID: 20076499
External Links
PubMed source DOI: 10.1371/journal.pbio.0040370 PMC Full Text View journal details
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