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. | PubMed

Qifei Cong¹, Breeanne M Soteros¹, Mackenna Wollet², Jun Hee Kim², Gek-Ming Sia³

1. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
2. Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
3. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. siag@uthscsa.edu.

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.

Presented By Breeanne M Soteros | ORCID iD