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

Qifei Cong, Breeanne M. Soteros, Mackenna Wollet, Jun Hee Kim, Gek Ming Sia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1067-1078
Number of pages12
JournalNature Neuroscience
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Neuroscience(all)

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