Complement: The Emerging Architect of the Developing Brain

• Published in: Trends in neurosciences (Regular ed.) Vol. 41; no. 6; pp. 373 - 384
• Main Authors: Coulthard, Liam G., Hawksworth, Owen A., Woodruff, Trent M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2018
• Subjects: complement; innate immunity; neural progenitor; neurodevelopment; neuronal migration; synaptic pruning; neural progenitor; innate immunity; neurodevelopment; complement; neuronal migration; synaptic pruning
• ISSN: 0166-2236; 1878-108X
• DOI: 10.1016/j.tins.2018.03.009

Complement activation products have long been associated with roles in the innate immune system, linking the humoral and cellular responses. However, among their recently described non-inflammatory roles, complement proteins also have multiple emerging novel functions in brain development. Within this context, separate proteins and pathways of complement have carved out physiological niches in the formation, development, and refinement of neurons. They demonstrate actions that are both reminiscent of peripheral immune actions and removed from them. We review here three key roles for complement proteins in the developing brain: progenitor proliferation, neuronal migration, and synaptic pruning. Some proteins traditionally associated with the complement cascade of innate immunity have novel functions during brain development. The C5a–C5aR1 signaling axis maintains cell polarity in the ventricular zone through PKCζ. Impaired C5aR1 signaling during neurodevelopment can lead to behavioral deficits in the adult. Migration of neurons from the ventricular zone to the cortical plate is a process that is dependent on the lectin complement pathway. Knockout of MASP1/2 causes cortical layering deficits which can be rescued through restoration of downstream complement signaling. The classical complement cascade is required for normal postnatal synaptic pruning. C3b–CR3 interaction allows microglial engulfment of low-activity synapses.