The Classical Complement Cascade Mediates CNS Synapse Elimination

Beth Stevens, Nicola J. Allen, Luis E. Vazquez, Gareth R. Howell, Karen S. Christopherson, Navid Nouri, Kristina D. Micheva, Adrienne K. Mehalow, Andrew D. Huberman, Benjamin Stafford, Alexander Sher, Alan M M. Litke, John D. Lambris, Stephen J. Smith, Simon W.M. John, Ben A. Barres

Research output: Contribution to journalArticle

1371 Scopus citations

Abstract

During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)1164-1178
Number of pages15
JournalCell
Volume131
Issue number6
DOIs
StatePublished - Dec 14 2007
Externally publishedYes

Keywords

  • CELLIMMUNO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., Sher, A., Litke, AM. M., Lambris, J. D., Smith, S. J., John, S. W. M., & Barres, B. A. (2007). The Classical Complement Cascade Mediates CNS Synapse Elimination. Cell, 131(6), 1164-1178. https://doi.org/10.1016/j.cell.2007.10.036