In 2012, Beth Stevens, Ph.D., and her lab at Boston Children's Hospital showed that microglia, immune cells that live in the brain, prune back unwanted synapses by engulfing or "eating" them. They also identified a set of "eat me" signals required to promote this process: complement proteins, best known for helping the immune system combat infection. Now, in new work published today in Neuron, Stevens and colleagues reveal the flip side: a "don't eat me" signal that prevents microglia from pruning useful connections away. The signal, a protein called CD47, communicates with a receptor on microglia called SIRP alpha.
"We think this is first evidence of a protective cue that microglia can read out that tells them not to prune," says Stevens. "Our findings demonstrate that synaptic protection is necessary to ensure normal brain development."
Like complement, CD47 also plays a role in the immune system, where it is part of a group of "don't eat me" signals that prevent damage or removal of healthy cells in situations of infection or challenge by pathogens. (In fact, some cancer immunotherapies work by inhibiting CD47, encouraging the immune system to attack cancer cells.)
"We asked, are any of these molecules expressed in the brain?" says Stevens. "Sure enough, CD47 is expressed very highly and is found throughout the brain. We think that, as seen following an immune challenge, the brain is using it as a protective cue, telling microglia not to prune specific synapse. The brain and the immune system are sharing signals in a way that we're only beginning to appreciate."
To model synapse development and pruning in the brain, Stevens and colleagues tapped a time-tested model of synapse refinement: the developing visual system. They found that during the time when synapse pruning in the visual system is at its peak, CD47 is enriched in the developing visual thalamus and localized to synapses. They also found that mice lacking CD47 had increased pruning activity by microglia and fewer synapses than normal mice, having lost the "don't eat me" signal.
"The study is exciting because it suggests a possible cooperative interaction between 'eat me' and 'don't eat me' signals that instruct microglia what to do when they see a synapse," says Stevens. "As we start to delve deeper and identify new molecules and mechanisms by which microglia are pruning, it's important to think how all these things fit together. It's not one pathway, but a coordinated effort."