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.

  • Progress
  • Published:

C1q: the perfect complement for a synaptic feast?

Nature Reviews Neuroscience volume 9, pages 807–811 (2008)Cite this article

Abstract

The efficient and selective removal of apoptotic cells is an important feature of tissue development, homeostasis and pathology. In the nervous system, synapses and distal axons are selectively eliminated as part of the remodelling that underpins development and pathology, through a process that has some features in common with apoptotic cell removal. Components of the complement cascade are implicated in the efficient removal of apoptotic cells outside the nervous system, and recent evidence suggests that the complement components C1q and C3 have a role in the selective tagging of supernumerary synapses in the developing visual system and in their efficient removal by as yet unidentified cells.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Adapting a classical complement cascade for synaptic pruning.
Figure 2: Segregation of retinal projections to the lateral geniculate nucleus (LGN).
Figure 3: Complement targeting and accumulation at synapses requires specific receptors.

Similar content being viewed by others

References

  1. Low, L. K. & Cheng, H. J. A little nip and tuck: axon refinement during development and axonal injury. Curr. Opin. Neurobiol. 15, 549–556 (2005).

    Article  CAS  Google Scholar 

  2. Luo, L. & O'Leary, D. D. Axon retraction and degeneration in development and disease. Ann. Rev. Neurosci. 28, 127–156 (2005).

    Article  CAS  Google Scholar 

  3. Perry, V. H., Hume, D. A. & Gordon S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313–326 (1985).

    Article  CAS  Google Scholar 

  4. Conforti, L., Adalbert, R. & Coleman, M. P. Neuronal death: where does the end begin? Trends Neurosci. 30, 159–166 (2007).

    Article  CAS  Google Scholar 

  5. Goddard, C. A., Butts, D. A. & Shatz, C. J. Regulation of CNS synapses by neuronal MHC class 1. Proc. Natl Acad. Sci. USA 104, 6828–6833 (2007).

    Article  Google Scholar 

  6. Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

    Article  CAS  Google Scholar 

  7. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19, 56–59 (1998).

    Article  CAS  Google Scholar 

  8. De Almeida, C. J. & Linden, R. Phagocytosis of apoptotic cells: matter of balance. Cell. Mol. Life Sci. 62, 1532–1546 (2005).

    Article  CAS  Google Scholar 

  9. Bredesen, D. E., Rao, R. V. & Mehlen, P. Cell death in the nervous system. Nature 443, 796–802 (2006).

    Article  CAS  Google Scholar 

  10. Trouw, L. A., Blom, A. M. & Gasque, P. Role of complement regulators in the removal of apoptotic cells. Mol. Immunol. 45, 1199–1207 (2008).

    Article  CAS  Google Scholar 

  11. Arlaud, G. J. et al. Structural biology of the C1 complex of complement unveils the mechanism of its activation and proteolytic activity. Mol. Immunol. 39, 383–394 (2001).

    Article  Google Scholar 

  12. Mollnes, T. E., Song, W. C. & Lambris, J. D. Complement in inflammatory tissue damage and disease. Trends Immunol. 23, 61–64 (2002).

    Article  CAS  Google Scholar 

  13. Yi, J. J. & Ehlers, M. D. Ubiquitin and protein turnover in synapse function. Neuron 47, 5629–5632 (2005).

    Article  Google Scholar 

  14. Cunningham, C. et al. Synaptic changes characterise early behavioural signs in the ME7 model of murine prion disease. Eur. J. Neurosci. 17, 2147–2155 (2003).

    Article  CAS  Google Scholar 

  15. Jaubert-Miazza, L. et al. Structural and functional composition of the developing retinogeniculate pathway in the mouse. Vis. Neurosci. 22, 661–676 (2005).

    Article  Google Scholar 

  16. Sanes, J. R. & Lichtman, J. W. Can molecules explain long-term potentiation? Nature Neurosci. 2, 597–604 (1999).

    Article  CAS  Google Scholar 

  17. Mack, T. G. et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nature Neurosci. 4, 1199–1206 (2001).

    Article  CAS  Google Scholar 

  18. Libby, R. T. et al. Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis. Neurosci. 22, 637–648 (2005).

    Article  Google Scholar 

  19. Beazley, L. D., Perry, V. H., Baker, B. & Darby, J. E. An investigation into the role of ganglion cells in the regulation of division and death of other retinal cells. Brain Res. 430, 169–184 (1987).

    Article  CAS  Google Scholar 

  20. Agrawal, A., Shrive A. K., Greenhough, T. J. & Volanakis, J. E. Topology and structure of the C1q-binding site on C-reactive protein. J. Immunol. 166, 3998–4004 (2001).

    Article  CAS  Google Scholar 

  21. Xu, D. et al. Narp and NP1 form heterocomplexes that function in development and activity dependent synaptic plasticity. Neuron 39, 513–528 (2003).

    Article  CAS  Google Scholar 

  22. O'Brien, R. J. et al. Synaptically targeted narp plays an essential role in the aggregation of AMPA receptors at excitatory synapses in cultured spinal neurons. J. Neurosci. 22, 4487–4498 (2002).

    Article  CAS  Google Scholar 

  23. Sia, G.-M., Belque, J., Rumbaugh, G., Cho, R. & Worley, P. F. Interaction of the N-terminal domain of AMPA receptor GluR4 subunit with neuronal pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55, 87–102 (2007).

    Article  CAS  Google Scholar 

  24. Bjartmar, L. et al. Neuronal pentraxins mediate synaptic refinement in the developing visual system. J. Neurosci. 26, 6269–6281 (2006).

    Article  CAS  Google Scholar 

  25. Gasque, P., Dean, Y. D., McGreal, E. P., VanBeek, J. & Morgan, B. P. Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49, 171–186 (2000).

    Article  CAS  Google Scholar 

  26. Kreutzberg, G. W., Graeber, M. B. & Streit, W. J. Neuron-glial relationship during regeneration of motorneurons. Metab. Brain Dis. 4, 81–85 (1989).

    Article  CAS  Google Scholar 

  27. Svensson, M. & Aldskogius, H. Synaptic density of axotomized hypoglossal motorneurons following pharmacological blockade of the microglial cell proliferation. Exp. Neurol. 120, 123–131 (1993).

    Article  CAS  Google Scholar 

  28. Kalla, R. et al. Microglia and the early phase immune surveillance in the axotimized facial motor nucleus: impaired microglial activation and lymphocyte recruitment but no effect on neuronal survival or axonal regeneration in macrophage-colony stimulating factor deficent mice. J. Comp. Neurol. 436, 182–201 (2001).

    Article  CAS  Google Scholar 

  29. Sikorska, B., Liberski, P. P., Giraud, P., Kopp, N. & Brown, P. Autophagy is a part of ultrastructural synaptic pathology in Creutzfeldt–Jakob disease: a brain biopsy study. Int. J. Biochem. Cell Biol. 36, 2563–2573 (2004).

    Article  CAS  Google Scholar 

  30. Ronnevi, L. O. Origin of glial processes responsible for the spontaneous postnatal phagocytosis of boutons on cat spinal motoneurons. Cell Tissue Res. 189, 203–217 (1978).

    Article  CAS  Google Scholar 

  31. Halassa, M. M., Fellin, T. & Haydon, P. G. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol. Med. 13, 54–63 (2007).

    Article  CAS  Google Scholar 

  32. Husemann J., Loike, J. D., Anankov, R., Febbraio, M. & Silverstein, S. C. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, 195–205 (2002).

    Article  Google Scholar 

  33. Ronnevi, L. O. Spontaneous phagocytosis of C-type synaptic terminals by spinal α-motoneurons in newborn kittens. An electron microscopic study. Brain Res. 162, 189–199 (1979).

    Article  CAS  Google Scholar 

  34. Bowen, S. et al. The phagocytic capacity of neurones. Eur. J. Neurosci. 25, 2947–2955 (2007).

    Article  Google Scholar 

  35. Schraufstatter, I. U., Trieu, K., Sikora, L., Sriramarao, P. & DiScipio, R. Complement C3a and C5a induce different signal transduction cascades in endothelial cells. J. Immunol. 169, 2102–2110 (2002).

    Article  CAS  Google Scholar 

  36. Bishop, D. L., Misgeld, T., Walsh, M. K., Gan, W. B. & Lichtman, J. W. Axon branch removal at developing synapses by axosome shedding. Neuron 44, 651–661 (2004).

    Article  CAS  Google Scholar 

  37. Lobsiger, C. S., Boillée, S. & Cleveland, D. W. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc. Natl. Acad. Sci. USA 104, 7319–7326 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Teeling for valuable discussions on the manuscript. Studies on synaptic degeneration in the authors' laboratories are supported by the Medical Research Council (UK).

Author information

Authors and Affiliations

  1. V. Hugh Perry and Vincent O'Connor are at the School of Biological Sciences, University of Southampton, Southampton, SO16 7PX, UK. vhp@soton.ac.uk,

    V. Hugh Perry & Vincent O'Connor

Authors
  1. V. Hugh Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincent O'Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Author's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perry, V., O'Connor, V. C1q: the perfect complement for a synaptic feast?. Nat Rev Neurosci 9, 807–811 (2008). https://doi.org/10.1038/nrn2394

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2394

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