Skip to main content
SpringerLink
Log in

Synapse Loss, Synaptic Plasticity and the Postsynaptic Density

  • Chapter
Synaptic Plasticity and the Mechanism of Alzheimer's Disease

Part of the book series: Research and Perspectives in Alzheimer's Disease ((ALZHEIMER))

  • 918 Accesses

Abstract

Excitatory synapses of the mammalian brain usually occur on dendritic spines, the postsynaptic compartment of most excitatory synapses. The postsynaptic membrane contains a high concentration of NMDA receptors (NMDARs) and AMPA receptors (AMPARs) as well as their associatedsignalingproteins,whichareassembledbyscaffoldproteins into thepostsynaptic density (PSD). Composed of hundreds of distinct proteins, the PSD dynamically changes its structure and composition in response to synaptic activity. A comprehensive, quantitative and three-dimensional view of PSD architecture is gradually emerging, providing unprecedented details on the protein composition and stoichiometry of the PSD. Such knowledge facilitates understanding of the postsynaptic signaling mechanisms that control the strengthening and growth versus the weakening and loss of synapses. Themolecular organization of the PSDreveals several signalingpathways that likely mediate synapticdepressionandsynapse elimination.These signaling pathways might be relevant to the pathogenesis of Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Apperson ML, Moon IS, Kennedy MB (1996) Characterization of densin-180, a new brain-specific synaptic protein of the O-sialoglycoprotein family. J Neurosci 16:6839–6852.

    PubMed  CAS  Google Scholar 

  • Bingol B, Schuman EM (2006) Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441:1144–1148.

    Article  PubMed  CAS  Google Scholar 

  • Borgdorff AJ, Choquet D (2002) Regulation of AMPA receptor lateral movements. Nature 417:649–653.

    Article  PubMed  CAS  Google Scholar 

  • Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31:680–686.

    Article  PubMed  CAS  Google Scholar 

  • Carlin RK, Grab DJ, Cohen RS, Siekevitz P (1980) Isolation and characterization of postsynaptic densities from various brain regions: enrichment of different types of postsynaptic densities. J Cell Biol 86:831–845.

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Vinade L, Leapman RD, Petersen JD, Nakagawa T, Phillips TM, Sheng M, Reese TS (2005) Mass of the postsynaptic density and enumeration of three key molecules. Proc Natl Acad Sci USA 102:11551–11556.

    Article  PubMed  CAS  Google Scholar 

  • Cheng D, Hoogenraad CC, Rush J, Ramm E, Schlager MA, Duong DM, Xu P, Wijayawardana SR, Hanfelt J, Nakagawa T, Sheng M, Peng J (2006) Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum. Mol Cell Proteomics 5:1158–1170.

    Article  PubMed  CAS  Google Scholar 

  • Chklovskii DB, Mel BW, Svoboda K (2004) Cortical rewiring and information storage. Nature 431:782–788.

    Article  PubMed  CAS  Google Scholar 

  • Cho KO, Hunt CA, Kennedy MB (1992) The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. Neuron 9:929–942.

    Article  PubMed  CAS  Google Scholar 

  • Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK, Lu H, Bear MF, Scott JD (2003) Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40:595–607.

    Article  PubMed  CAS  Google Scholar 

  • Collins MO, Yu L, Coba MP, Husi H, Campuzano I, Blackstock WP, Choudhary JS, Grant SG (2005) Proteomic analysis of in vivo phosphorylated synaptic proteins. J Biol Chem 280:5972–5982.

    Article  PubMed  CAS  Google Scholar 

  • Collins MO, Husi H, Yu L, Brandon JM, Anderson CN, Blackstock WP, Choudhary JS, Grant SG (2006) Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J Neurochem 97 Suppl 1:16–23

    Article  Google Scholar 

  • Cowan WM, Fawcett JW, O’Leary DD, Stanfield BB (1984) Regressive events in neurogenesis. Science 225:1258–1265.

    Article  PubMed  CAS  Google Scholar 

  • Dosemeci A, Tao-Cheng JH, Vinade L, Winters CA, Pozzo-Miller L, Reese TS (2001) Glutamate-induced transient modification of the postsynaptic density. Proc Natl Acad Sci USA 98:10428–10432.

    Article  PubMed  CAS  Google Scholar 

  • Dosemeci A, Tao-Cheng JH, Vinade L, Jaffe H (2006) Preparation of postsynaptic density fraction from hippocampal slices and proteomic analysis. Biochem Biophys Res Commun 339:687–694.

    Article  PubMed  CAS  Google Scholar 

  • Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature Neurosci 6:231–242.

    Article  PubMed  CAS  Google Scholar 

  • Elias GM, Funke L, Stein V, Grant SG, Bredt DS, Nicoll RA (2006) Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 52:307–320.

    Article  PubMed  CAS  Google Scholar 

  • Ethell IM, Pasquale EB (2005) Molecular mechanisms of dendritic spine development and remodeling. Prog Neurobiol 75:161–205.

    Article  PubMed  CAS  Google Scholar 

  • Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Brain Res Rev 39:29–54.

    Article  PubMed  Google Scholar 

  • Fu Z, Lee SH, Simonetta A, Hansen J, Sheng M, Pak DT (2007) Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons. J Neurochem 100:118–131.

    Article  PubMed  CAS  Google Scholar 

  • Funke L, Dakoji S, Bredt DS (2005) Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu Rev Biochem 74:219–245.

    Article  PubMed  CAS  Google Scholar 

  • Goda Y, Davis GW (2003) Mechanisms of synapse assembly and disassembly. Neuron 40:243–264.

    Article  PubMed  CAS  Google Scholar 

  • Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1–49.

    Article  PubMed  CAS  Google Scholar 

  • Hayashi Y, Majewska AK (2005) Dendritic spine geometry: functional implication and regulation. Neuron 46:529–532.

    Article  PubMed  CAS  Google Scholar 

  • Holtmaat A, Wilbrecht L, Knott GW, Welker E, Svoboda K (2006) Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441:979–983.

    Article  PubMed  CAS  Google Scholar 

  • Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843.

    Article  PubMed  CAS  Google Scholar 

  • Hu BR, Park M, Martone ME, Fischer WH, Ellisman MH, Zivin JA (1998) Assembly of proteins to postsynaptic densities after transient cerebral ischemia. J Neurosci 18:625–633.

    PubMed  CAS  Google Scholar 

  • Huang CC, You JL, Wu MY, Hsu KS (2004) Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem 279:12286–12292.

    Article  PubMed  CAS  Google Scholar 

  • Husi H, Grant SG (2001) Proteomics of the nervous system. Trends Neurosci 24:259–266.

    Article  PubMed  CAS  Google Scholar 

  • Husi H,Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nature Neurosci 3:661–669.

    Article  PubMed  CAS  Google Scholar 

  • Imamura Y, Matsumoto N, Kondo S, Kitayama H, Noda M (2003) Possible involvement of Rap1 and Ras in glutamatergic synaptic transmission. Neuroreport 14:1203–1207.

    Article  PubMed  CAS  Google Scholar 

  • Inoue A, Okabe S (2003) The dynamic organization of postsynaptic proteins: translocating molecules regulate synaptic function. Curr Opin Neurobiol 13:332–340.

    Article  PubMed  CAS  Google Scholar 

  • Jordan BA, Fernholz BD, Boussac M, Xu C, Grigorean G, Ziff EB, Neubert TA (2004) Identification and verification of novel rodent postsynaptic density proteins. Mol Cell Proteomics 3:857–871.

    Article  PubMed  CAS  Google Scholar 

  • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937.

    Article  PubMed  CAS  Google Scholar 

  • Karpova A, Mikhaylova M, Thomas U, Knopfel T, Behnisch T (2006) Involvement of protein synthesis and degradation in long-term potentiation of Schaffer collateral CA1 synapses. J Neurosci 26:4949–4955.

    Article  PubMed  CAS  Google Scholar 

  • Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H (2003) Structure-stability-function relationships of dendritic spines. Trends Neurosci 26:360–368.

    Article  PubMed  CAS  Google Scholar 

  • Kauselmann G, Weiler M, Wulff P, Jessberger S, Konietzko U, Scafidi J, Staubli U, Bereiter-Hahn J, Strebhardt K, Kuhl D (1999) The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. Embo J 18:5528–5539.

    Article  PubMed  CAS  Google Scholar 

  • Kennedy MB (2000) Signal-processing machines at the postsynaptic density. Science 290:750–754.

    Article  PubMed  CAS  Google Scholar 

  • Kennedy MB, Bennett MK, Erondu NE (1983) Biochemical and immunochemical evidence that the “major postsynaptic density protein” is a subunit of a calmodulin-dependent protein kinase. Proc Natl Acad Sci USA 80:7357–7361.

    Article  PubMed  CAS  Google Scholar 

  • Kennedy MB, Beale HC, Carlisle HJ, Washburn LR (2005) Integration of biochemical signalling in spines. Nature Rev Neurosci 6:423–434.

    Article  CAS  Google Scholar 

  • Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nature Rev Neurosci 5:771–781.

    Article  CAS  Google Scholar 

  • Kim MJ, Dunah AW, Wang YT, Sheng M (2005) Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 46:745–760.

    Article  PubMed  CAS  Google Scholar 

  • Lichtman JW, Colman H (2000) Synapse elimination and indelible memory. Neuron 25:269–278.

    Article  PubMed  CAS  Google Scholar 

  • Machida N, Umikawa M, Takei K, Sakima N, Myagmar BE, Taira K, Uezato H, Ogawa Y, Kariya KI (2004) Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase. J Biol Chem 279:15711–15714

    Article  PubMed  CAS  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21.

    Article  PubMed  CAS  Google Scholar 

  • Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126.

    Article  PubMed  CAS  Google Scholar 

  • Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H (2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429:761–766.

    Article  PubMed  CAS  Google Scholar 

  • Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O’Dell TJ, Grant SG (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396:433–439.

    Article  PubMed  CAS  Google Scholar 

  • Morozov A, Muzzio IA, Bourtchouladze R, Van-Strien N, Lapidus K, Yin D, Winder DG, Adams JP, Sweatt JD, Kandel ER (2003) Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory. Neuron 39:309–325.

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Walz T, Hayashi Y, Sheng M (2004) Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44:453–467.

    Article  PubMed  CAS  Google Scholar 

  • Nimchinsky EA, Yasuda R, Oertner TG, Svoboda K (2004) The number of glutamate receptors opened by synaptic stimulation in single hippocampal spines. J Neurosci 24:2054–2064.

    Article  PubMed  CAS  Google Scholar 

  • O’Leary DD, Koester SE (1993) Development of projection neuron types, axon pathways, and patterned connections of the mammalian cortex. Neuron 10:991–1006.

    Article  PubMed  CAS  Google Scholar 

  • Pak DT, Sheng M (2003) Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science 302:1368–1373.

    Article  PubMed  CAS  Google Scholar 

  • Pak DT, Yang S, Rudolph-Correia S, Kim E, Sheng M (2001) Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31:289–303.

    Article  PubMed  CAS  Google Scholar 

  • Peng J, Kim MJ, Cheng D, Duong DM, Gygi SP, Sheng M (2004) Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry. J Biol Chem 279:21003–21011.

    Article  PubMed  CAS  Google Scholar 

  • Petersen JD, Chen X, Vinade L, Dosemeci A, Lisman JE, Reese TS (2003) Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD. J Neurosci 23:11270–11278.

    PubMed  CAS  Google Scholar 

  • Satoh K, Takeuchi M, Oda Y, Deguchi-Tawarada M, Sakamoto Y, Matsubara K, Nagasu T, Takai Y (2002) Identification of activity-regulated proteins in the postsynaptic density fraction. Genes Cells 7:187–197.

    Article  PubMed  CAS  Google Scholar 

  • Sheng M, Kim MJ (2002) Postsynaptic signaling and plasticity mechanisms. Science 298:776–780.

    Article  PubMed  CAS  Google Scholar 

  • Siekevitz P (1985) The postsynaptic density: a possible role in long-lasting effects in the central nervous system. Proc Natl Acad Sci USA 82:3494–3498.

    Article  PubMed  CAS  Google Scholar 

  • Sorra KE, Harris KM (2000) Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines. Hippocampus 10:501–511.

    Article  PubMed  CAS  Google Scholar 

  • Star EN, Kwiatkowski DJ, Murthy VN (2002) Rapid turnover of actin in dendritic spines and its regulation by activity. Nature Neurosci 5:239–246.

    Article  PubMed  CAS  Google Scholar 

  • Stork PJ (2003) Does Rap1 deserve a bad Rap? Trends Biochem Sci 28:267–275.

    Article  PubMed  CAS  Google Scholar 

  • Sugiyama Y, Kawabata I, Sobue K, Okabe S (2005) Determination of absolute protein numbers in single synapses by a GFP-based calibration technique. Nature Meth 2:677–684.

    Article  CAS  Google Scholar 

  • Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95–101.

    Article  PubMed  CAS  Google Scholar 

  • Triller A, Choquet D (2005) Surface trafficking of receptors between synaptic and extrasynaptic membranes: and yet they do move! Trends Neurosci 28:133–139.

    Article  PubMed  CAS  Google Scholar 

  • Tsuriel S, Geva R, Zamorano P, Dresbach T, Boeckers T, Gundelfinger ED, Garner CC, Ziv NE (2006) Local sharing as a predominant determinant of synaptic matrix molecular dynamics. PLoS Biol 4:e271.

    Article  PubMed  Google Scholar 

  • Walikonis RS, Jensen ON, Mann M, Provance DW Jr., Mercer JA, Kennedy MB (2000) Identification of proteins in the postsynaptic density fraction by mass spectrometry. J Neurosci 20:4069–4080.

    Google Scholar 

  • Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44:181–193.

    Article  PubMed  CAS  Google Scholar 

  • Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539.

    Article  PubMed  CAS  Google Scholar 

  • Walsh MJ, Kuruc N (1992) The postsynaptic density: constituent and associated proteins characterized by electrophoresis, immunoblotting, and peptide sequencing. J Neurochem 59:667–678.

    Article  PubMed  CAS  Google Scholar 

  • Weimann JM, Zhang YA, Levin ME, Devine WP, Brulet P, McConnell SK (1999) Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron 24:819–831.

    Article  PubMed  CAS  Google Scholar 

  • Xie Z, Huganir RL, Penzes P (2005) Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6. Neuron 48:605–618.

    Article  PubMed  CAS  Google Scholar 

  • Yoshimura Y, Yamauchi Y, Shinkawa T, Taoka M, Donai H, Takahashi N, Isobe T, Yamauchi T (2004) Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography-tandem mass spectrometry. J Neurochem 88:759–768.

    Article  PubMed  CAS  Google Scholar 

  • Yuste R, Bonhoeffer T. (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071–1089.

    Article  Google Scholar 

  • Zhang W, Vazquez L, Apperson M, Kennedy MB, (1999) Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. J Neurosci 19:96–108.

    PubMed  CAS  Google Scholar 

  • Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:443–455.

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Pak D, Qin Y, McCormack SG, Kim MJ, Baumgart JP, Velamoor V, Auberson YP, Osten P, van Aelst, L, Sheng M, Zhu JJ (2005). Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 46:905–916.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, Depts of Brain and Cognitive Sciences, and Biology, Massachusetts Institute of Technology, Cambridge, USA

    Morgan Sheng

  2. The Picower Institute for Learning and Memory, Massachusetts Institute of Technology 77, Correspondence to: Morgan Sheng, MassachusettsAvenue (46-4303), 02139, Cambridge, MA , USA

    Morgan Sheng

Authors
  1. Morgan Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Neurologic Diseases, Brigham andWomen’s Ho, Harvard Medical School, 02115, Boston, MA, USA

    Dennis J. Selkoe

  2. Laboratoire de Biologie Cellulaire de la Synapse, Institut National de la Santé et de la Recherche, Médicale Unite 789, 46 rue d’Ulm, 75005, Paris, France

    Antoine Triller

  3. Pour la Recherche Thérapeutique, Fondation IPSEN, 24, rue Erlanger, 75781, Paris Cedex 16, France

    Yves Christen

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Sheng, M. (2008). Synapse Loss, Synaptic Plasticity and the Postsynaptic Density. In: Selkoe, D., Triller, A., Christen, Y. (eds) Synaptic Plasticity and the Mechanism of Alzheimer's Disease. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-76330-7_4

Download citation

Publish with us

Policies and ethics

Search

Navigation