The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development

Nat Neurosci. 2020 Sep;23(9):1067-1078. doi: 10.1038/s41593-020-0672-0. Epub 2020 Jul 13.


Complement-mediated synapse elimination has emerged as an important process in both brain development and neurological diseases, but whether neurons express complement inhibitors that protect synapses against complement-mediated synapse elimination remains unknown. Here, we show that the sushi domain protein SRPX2 is a neuronally expressed complement inhibitor that regulates complement-dependent synapse elimination. SRPX2 directly binds to C1q and blocks its activity, and SRPX2-/Y mice show increased C3 deposition and microglial synapse engulfment. They also show a transient decrease in synapse numbers and increase in retinogeniculate axon segregation in the lateral geniculate nucleus. In the somatosensory cortex, SRPX2-/Y mice show decreased thalamocortical synapse numbers and increased spine pruning. C3-/-;SRPX2-/Y double-knockout mice exhibit phenotypes associated with C3-/- mice rather than SRPX2-/Y mice, which indicates that C3 is necessary for the effect of SRPX2 on synapse elimination. Together, these results show that SRPX2 protects synapses against complement-mediated elimination in both the thalamus and the cortex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / embryology*
  • Brain / metabolism
  • Complement Activation / physiology
  • Complement System Proteins*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neurogenesis / physiology*
  • Neuronal Plasticity / physiology*


  • Membrane Proteins
  • Srpx protein, mouse
  • Complement System Proteins