Complement System in Neural Synapse Elimination in Development and Disease

Adv Immunol. 2017;135:53-79. doi: 10.1016/bs.ai.2017.06.004. Epub 2017 Jul 31.

Abstract

Recent discoveries implicate the classical complement cascade in normal brain development and in disease. Complement proteins C1q, C3, and C4 participate in synapse elimination, tagging inappropriate synaptic connections between neurons for removal by phagocytic microglia that exist in a special, highly phagocytic state during the synaptic pruning period. Several neurodevelopmental disorders, such as schizophrenia and autism, are thought to be caused by an imbalance in synaptic pruning, and recent studies suggest that dysregulation of complement could promote this synaptic pruning imbalance. Moreover, in the mature brain, complement can be aberrantly activated in early stages of neurodegenerative diseases to stimulate synapse loss. Similar pathways can also be activated in response to inflammation, as in West Nile Virus infection or in lupus, where peripheral inflammation can promote microglia-mediated synapse loss. Whether synapse loss in disease is a true reactivation of developmental synaptic pruning programs remains unclear; nonetheless, complement proteins represent potential therapeutic targets for both neurodevelopmental and neurodegenerative diseases.

Keywords: Complement C4; Lupus; Microglia; Neurodegeneration; Schizophrenia; Synaptic pruning; Type I IFN.

Publication types

  • Review

MeSH terms

  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / immunology
  • Autistic Disorder / pathology
  • Complement System Proteins / genetics
  • Complement System Proteins / immunology*
  • Epilepsy / genetics
  • Epilepsy / immunology
  • Epilepsy / pathology
  • Gene Expression Regulation, Developmental
  • Humans
  • Microglia / immunology
  • Microglia / pathology
  • Nerve Net / immunology*
  • Nerve Net / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / immunology
  • Neurogenesis / genetics
  • Neurogenesis / immunology*
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / immunology*
  • Neurons / immunology
  • Neurons / pathology
  • Schizophrenia / genetics
  • Schizophrenia / immunology
  • Schizophrenia / pathology
  • Synapses / genetics
  • Synapses / immunology*
  • Synapses / pathology
  • Synaptic Transmission

Substances

  • Nerve Tissue Proteins
  • Complement System Proteins