Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Evolutionary expansion and anatomical specialization of synapse proteome complexity

Nature Neuroscience volume 11, pages 799–806 (2008)Cite this article

Abstract

Understanding the origins and evolution of synapses may provide insight into species diversity and the organization of the brain. Using comparative proteomics and genomics, we examined the evolution of the postsynaptic density (PSD) and membrane-associated guanylate kinase (MAGUK)-associated signaling complexes (MASCs) that underlie learning and memory. PSD and MASC orthologs found in yeast carry out basic cellular functions to regulate protein synthesis and structural plasticity. We observed marked changes in signaling complexity at the yeast-metazoan and invertebrate-vertebrate boundaries, with an expansion of key synaptic components, notably receptors, adhesion/cytoskeletal proteins and scaffold proteins. A proteomic comparison of Drosophila and mouse MASCs revealed species-specific adaptation with greater signaling complexity in mouse. Although synaptic components were conserved amongst diverse vertebrate species, mapping mRNA and protein expression in the mouse brain showed that vertebrate-specific components preferentially contributed to differences between brain regions. We propose that the evolution of synapse complexity around a core proto-synapse has contributed to invertebrate-vertebrate differences and to brain specialization.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparison of PSD and MASC homologs and expansion of selected functional groups of genes.
Figure 2: Proteomic analysis of the Drosophila MASC.
Figure 3: Variation in expression patterns in mouse brain regions.
Figure 4: Summary of relationships of synaptic proteome evolution with neuronal number, behavior and expression patterns.

Similar content being viewed by others

References

  1. Kandel, E.R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    Article  CAS  Google Scholar 

  2. Moore, B.R. The evolution of learning. Biol. Rev. Camb. Philos. Soc. 79, 301–335 (2004).

    Article  Google Scholar 

  3. Roth, G. & Dicke, U. Evolution of the brain and intelligence. Trends Cogn. Sci. 9, 250–257 (2005).

    Article  Google Scholar 

  4. Cuthbert, P.C. et al. Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies. J. Neurosci. 27, 2673–2682 (2007).

    Article  CAS  Google Scholar 

  5. Komiyama, N.H. et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity and learning in the complex with postsynaptic density 95 and NMDA receptor. J. Neurosci. 22, 9721–9732 (2002).

    Article  CAS  Google Scholar 

  6. Migaud, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density–95 protein. Nature 396, 433–439 (1998).

    Article  CAS  Google Scholar 

  7. Sprengel, R. et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92, 279–289 (1998).

    Article  CAS  Google Scholar 

  8. Collins, M.O. et al. Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J. Neurochem. 97 Suppl 1, 16–23 (2006).

    Article  CAS  Google Scholar 

  9. Dosemeci, A. et al. Composition of the synaptic PSD-95 complex. Mol. Cell Proteomics 6, 1749–1760 (2007).

    Article  CAS  Google Scholar 

  10. Husi, H., Ward, M.A., Choudhary, J.S., Blackstock, W.P. & Grant, S.G. Proteomic analysis of NMDA receptor–adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669 (2000).

    Article  CAS  Google Scholar 

  11. Collins, M.O. et al. Proteomic analysis of in vivo phosphorylated synaptic proteins. J. Biol. Chem. 280, 5972–5982 (2005).

    Article  CAS  Google Scholar 

  12. Yamauchi, T. Molecular constituents and phosphorylation-dependent regulation of the postsynaptic density. Mass Spectrom. Rev. 21, 266–286 (2002).

    Article  CAS  Google Scholar 

  13. Yoshimura, Y. et al. Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography-tandem mass spectrometry. J. Neurochem. 88, 759–768 (2004).

    Article  CAS  Google Scholar 

  14. Grant, S.G., Marshall, M.C., Page, K.L., Cumiskey, M.A. & Armstrong, J.D. Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases. Hum. Mol. Genet. 14 Spec No. 2, R225–234 (2005).

    Article  CAS  Google Scholar 

  15. Laumonnier, F., Cuthbert, P.C. & Grant, S.G. The role of neuronal complexes in human X-linked brain diseases. Am. J. Hum. Genet. 80, 205–220 (2007).

    Article  CAS  Google Scholar 

  16. Pocklington, A.J., Cumiskey, M., Armstrong, J.D. & Grant, S.G.N. The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behavior. Mol. Syst. Biol. 2, E1–E14 (2006).

    Article  Google Scholar 

  17. Delsuc, F., Brinkmann, H., Chourrout, D. & Philippe, H. Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature 439, 965–968 (2006).

    Article  CAS  Google Scholar 

  18. Cyert, M.S. Genetic analysis of calmodulin and its targets in Saccharomyces cerevisiae. Annu. Rev. Genet. 35, 647–672 (2001).

    Article  CAS  Google Scholar 

  19. Elion, E.A., Qi, M. & Chen, W. Signal transduction. Signaling specificity in yeast. Science 307, 687–688 (2005).

    Article  CAS  Google Scholar 

  20. Erdman, S. & Snyder, M. A filamentous growth response mediated by the yeast mating pathway. Genetics 159, 919–928 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Harashima, T., Anderson, S., Yates, J.R., III & Heitman, J. The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Mol. Cell 22, 819–830 (2006).

    Article  CAS  Google Scholar 

  22. Palecek, S.P., Parikh, A.S. & Kron, S.J. Sensing, signalling and integrating physical processes during Saccharomyces cerevisiae invasive and filamentous growth. Microbiology 148, 893–907 (2002).

    Article  CAS  Google Scholar 

  23. Nichols, S.A., Dirks, W., Pearse, J.S. & King, N. Early evolution of animal cell signaling and adhesion genes. Proc. Natl. Acad. Sci. USA 103, 12451–12456 (2006).

    Article  CAS  Google Scholar 

  24. Sakarya, O. et al. A postsynaptic scaffold at the origin of the animal kingdom. PLoS ONE 2, e506 (2007).

    Article  Google Scholar 

  25. te Velthuis, A.J., Admiraal, J.F. & Bagowski, C.P. Molecular evolution of the MAGUK family in metazoan genomes. BMC Evol. Biol. 7, 129 (2007).

    Article  Google Scholar 

  26. Yasuyama, K., Meinertzhagen, I.A. & Schurmann, F.W. Synaptic organization of the mushroom body calyx in Drosophila melanogaster. J. Comp. Neurol. 445, 211–226 (2002).

    Article  Google Scholar 

  27. Ruiz-Canada, C., Koh, Y.H., Budnik, V. & Tejedor, F.J. DLG differentially localizes Shaker K+-channels in the central nervous system and retina of Drosophila. J. Neurochem. 82, 1490–1501 (2002).

    Article  CAS  Google Scholar 

  28. Husi, H. & Grant, S.G. Isolation of 2,000-kDa complexes of N-methyl-D-aspartate receptor and postsynaptic density–95 from mouse brain. J. Neurochem. 77, 281–291 (2001).

    Article  CAS  Google Scholar 

  29. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  30. Magdaleno, S. et al. BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system. PLoS Biol. 4, e86 (2006).

    Article  Google Scholar 

  31. Zapala, M.A. et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl. Acad. Sci. USA 102, 10357–10362 (2005).

    Article  CAS  Google Scholar 

  32. Lein, E.S., Zhao, X. & Gage, F.H. Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. J. Neurosci. 24, 3879–3889 (2004).

    Article  CAS  Google Scholar 

  33. Toledo-Rodriguez, M. et al. Correlation maps allow neuronal electrical properties to be predicted from single-cell gene expression profiles in rat neocortex. Cereb. Cortex 14, 1310–1327 (2004).

    Article  Google Scholar 

  34. Kutsuwada, T. et al. Impairment of suckling response, trigeminal neuronal pattern formation and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 16, 333–344 (1996).

    Article  CAS  Google Scholar 

  35. Sakimura, K. et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 373, 151–155 (1995).

    Article  CAS  Google Scholar 

  36. Ryan, T.J., Emes, R.D., Grant, S.G. & Komiyama, N.H. Evolution of NMDA receptor cytoplasmic interaction domains: implications for organization of synaptic signaling complexes. BMC Neurosci. 9, 6 (2008).

    Article  Google Scholar 

  37. Chung, H.J., Huang, Y.H., Lau, L.F. & Huganir, R.L. Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J. Neurosci. 24, 10248–10259 (2004).

    Article  CAS  Google Scholar 

  38. Li, B.S. et al. Regulation of NMDA receptors by cyclin-dependent kinase 5. Proc. Natl. Acad. Sci. USA 98, 12742–12747 (2001).

    Article  CAS  Google Scholar 

  39. Nakazawa, T. et al. NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity. EMBO J. 25, 2867–2877 (2006).

    Article  CAS  Google Scholar 

  40. Prybylowski, K. et al. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47, 845–857 (2005).

    Article  CAS  Google Scholar 

  41. Petralia, R.S., Sans, N., Wang, Y.X. & Wenthold, R.J. Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell. Neurosci. 29, 436–452 (2005).

    Article  CAS  Google Scholar 

  42. Sans, N. et al. A developmental change in NMDA receptor–associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000).

    Article  CAS  Google Scholar 

  43. Dorus, S. et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119, 1027–1040 (2004).

    Article  CAS  Google Scholar 

  44. Kasprzyk, A. et al. EnsMart: a generic system for fast and flexible access to biological data. Genome Res. 14, 160–169 (2004).

    Article  CAS  Google Scholar 

  45. Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 28, 263–266 (2000).

    Article  CAS  Google Scholar 

  46. Edgar, R.C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004).

    Article  CAS  Google Scholar 

  47. Guindon, S. & Gascuel, O. A simple, fast and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst. Biol. 52, 696–704 (2003).

    Article  Google Scholar 

  48. White, J.G., Southgate, E., Thomson, J.N. & Brenner, S. The structure of the nervous system of the nematode C. elegans. Phil. Trans. R. Soc. Lond. B 314, 1–340 (1986).

    Article  CAS  Google Scholar 

  49. Truman, J.W., Taylor, B.J. & Awad, T.A. in The Development of Drosophila melanogaster (eds. Bate, M. & Martinez Arias, A.) 1245–1276 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1993).

    Google Scholar 

  50. Imai, J.H. & Meinertzhagen, I.A. Neurons of the ascidian larval nervous system in Ciona intestinalis. I. Central nervous system. J. Comp. Neurol. 501, 316–334 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Hansen and L. Valor for assistance with array data, M. Marshall and K. Page for literature curation, A.J. Vilella, members of Genes to Cognition program for discussions and J.V. Turner for editorial assistance. This work was supported by the Wellcome Trust (C.N.G.A., J.D.A., R.D.E., M.O.C., M.D.R.C., J.S.C. and S.G.N.G.), the Medical Research Council (A.J.P. and R.D.E.), GlaxoSmithKline (B.R.M.), Edinburgh University and the e-Science Institute (J.D.A.), and the European Molecular Biology Organization (A.B.).

Author information

Author notes

  1. Richard D Emes, Andrew J Pocklington and Christopher N G Anderson: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Science and Technology in Medicine, Keele University, Thornburrow Drive, Stoke-on-Trent, ST4 7QB, Hartshill, UK

    Richard D Emes

  2. Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, 5 Forrest Hill, Edinburgh, EH1 2QL, UK

    Andrew J Pocklington, Bilal R Malik & J Douglas Armstrong

  3. Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, Cambridge, UK

    Christopher N G Anderson, Alex Bayes, Mark O Collins, Mike D R Croning, Jyoti S Choudhary & Seth G N Grant

  4. Division of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK

    Catherine A Vickers

  5. Okinawa Institute of Science and Technology, Neurobiology Research Unit, Suzaki, Uruma, Okinawa, Japan

    Catherine A Vickers

Authors
  1. Richard D Emes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew J Pocklington
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher N G Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alex Bayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark O Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Catherine A Vickers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mike D R Croning
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bilal R Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jyoti S Choudhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Douglas Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seth G N Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.D.E. conducted bioinformatic analysis of MASCs/PSDs and fMASCs. A.J.P. carried out bioinformatic and statistical analyses of MASCs/PSDs, fMASCs and expression datasets. C.N.G.A. and C.A.V. performed RNA and protein expression studies. B.R.M., A.B., M.O.C. and J.S.C. conducted fly proteomic studies. M.D.R.C. provided informatic support. R.D.E., A.J.P., C.G.N.A., J.D.A. and S.G.N.G. interpreted the results and prepared the manuscript. S.G.N.G. conceived and supervised the project.

Corresponding author

Correspondence to Seth G N Grant.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Methods (PDF 1558 kb)

Supplementary Table 1

NRC/MASC orthologs across 19 species. (XLS 172 kb)

Supplementary Table 2

PSD orthologs across 19 species. (XLS 484 kb)

Supplementary Table 3

Function of PSD/MASC orthologs in yeast. (XLS 105 kb)

Supplementary Table 4

PFAM domains present in PSD/MASC genes and their orthologs. (XLS 82 kb)

Supplementary Table 5

Composition and functional annotation of fMASC. (XLS 57 kb)

Supplementary Table 6

fMASC orthologs across 16 species. (XLS 164 kb)

Supplementary Table 7

Composition and functional annotation of mMASC/mPSD. (XLS 111 kb)

Supplementary Table 8

Anatomical expression patterns of synaptic proteins. (XLS 48 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Emes, R., Pocklington, A., Anderson, C. et al. Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat Neurosci 11, 799–806 (2008). https://doi.org/10.1038/nn.2135

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2135

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing