How the Immune System Sculpts Brain Circuitry
One of the major unsolved mysteries in neuroscience is how synapses are eliminated in the developing and diseased brain. During development synaptic pruning is required for precise brain wiring; however the mechanisms that drive the elimination of specific synapses remain elusive. Emerging evidence implicates resident phagocytes called microglia, and molecules traditionally associated with the immune system. Our recent studies support a model in which 'weaker' or less active synapses in the developing brain are targeted by complement proteins and then eliminated by phagocytic microglia that express receptors for complement and other immune molecules. These findings raise the question of how microglia differentiate the synapses or axons to prune from those to leave intact. Microglia-mediated synaptic refinement appears to depend on a careful balance of "eat me" (ie. complement) and a group of novel immune- related "don't eat me" signals. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in neurodegenerative and psychiatric disorders of synaptic dysfunction.