Emerging Roles of Complement in Psychiatric Disorders

Abstract

The complement system consists of more than 30 proteins that have long been known to participate to the immune defence against pathogens and to the removal of damaged cells. Their role, however, extends beyond immunity and clearance of altered "self" components in the periphery. In particular, complement proteins can be induced by all cell types in the brain. Recent discoveries highlight the role of complement in normal and pathological brain development. Specifically, the complement system mediates synaptic pruning, a developmental process whereby supernumerary synapses are eliminated in the immature brain. The complement system has been implicated in pathological synapse elimination in schizophrenia, West Nile virus infection, and lupus, all of which are associated with psychiatric manifestations. Complement also contributes to synapse loss in neurodegenerative conditions. This review provides a brief overview of the well-studied role of complement molecules in immunity. The contribution of complement to embryonic and adult neurogenesis, neuronal migration, and developmental synaptic elimination in the normal brain is reviewed. We discuss the role of complement in synapse loss in psychiatric and neurological diseases and evaluate the therapeutic potential of complement-targeting drugs for brain disorders.

Keywords: brain development; microglia; schizophrenia; synapse elimination; synaptic pruning.

Figure 1

The complement pathways. There are three distinct activation pathways in the complement system: the classical and lectin pathway that are activated by pathogens or damaged cells, and the alternative pathway that is activated by the spontaneous hydrolysis of C3. All lead to the sequential recruitment of complement components to form a C3 convertase (C4bC2b or C3bBb). The C3 convertase cleaves C3 into C3a and C3b. The C3b fragment binds to the surface of antigens, targeting them for opsonization (phagocytosis). C3b also induces a positive-feedback loop (“amplification loop”) leading to the generation of additional C3 convertase. C3b can also be recruited to become part of the C5 convertase, which cleaves C5 into C5a and C5b. The short C3a and C5a fragments, also known as anaphylatoxins, foster immune responses and inflammation. C5b initiates the assembly of C6, 7, 8, and 9 into the membrane attack complex, which forms a membrane pore resulting in the lysis of the pathogen.

Figure 2

Synapses elimination by microglia in normal and pathologic development. (A, B) During the course of postnatal development, supernumerary synapses are eliminated by microglia (upper panels). Complement components C1q, C4, and the C3 fragment iC3b tag inactive synapses. Microglial cells bind iC3b through their CR3 receptors and partially phagocyte tagged synapses, resulting in selective synapse elimination. High-activity synapses appear to be protected from synaptic pruning by an activity-dependent signal (bottom panels). (C) Synaptic pruning hypothesis in schizophrenia: high C4A expression in the schizophrenic human brain and the associated decrease in synapse density suggest increased complement activity resulting in an excess of iC3b-marked synapses and faulty synapse elimination (C).