We’re born with our brains prewired, but as information comes in from our environment, this circuitry is updated. A study from Boston Children’s Hospital provides a new glimpse of how this happens: Brain cells known as microglia, tuned into the crosstalk between neurons, literally engulf unnecessary connections, known as synapses, and prune them away.
The study, led by Beth Stevens, PhD, and Dori Schafer, PhD, of the Department of Neurology and the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, is the first to capture microglia, previously thought of as immune cells, in the act of eliminating synapses in the healthy, developing brain. The study further shows that microglia take their cues from neurons’ activity patterns and from a set of signals called the complement cascade, used by the immune system to rid the body of unwanted pathogens and debris. When complement signaling is disrupted, pruning of synapses is diminished.
The findings, reported online May 23 in the journal Neuron, may have implications for understanding neurodegenerative diseases in which synapses are lost, or developmental disorders such as autism in which synapses are dysfunctional.
Microglia were once thought to play mainly a supportive role in the brain, protecting against disease. Only recently have scientists begun to recognize their involvement in healthy brain development.
“They’re gatekeepers that are extremely responsive to changes in the environment,” says Stevens, senior investigator on the study. “They’re in the brain all the time it’s wiring up, and they can move and sense changes in activity.”
Stevens first showed in 2007 that defects in the complement system inhibit pruning of synapses, and that neurons are loaded with complement proteins soon after birth -- just when pruning is at its peak. In the new paper, she and Schafer demonstrate that microglia have receptors that recognize the complement protein C3 – the same protein found on synapses that are destined for elimination.
“We think that weaker synapses are being tagged with C3, and that microglia are eliminating them just as macrophages would eliminate bacteria,” says Schafer, first author on the paper. “C3 is like an ‘eat me’ signal.”
Mice lacking C3 receptors, or whose microglia had these receptors blocked with a drug, did not eliminate weaker synapses, the researchers showed.
Because microglia are so active, the researchers tracked their activity in mice, using dyes as tracers, and focused on the visual system connecting the eyes and brain, because it is well understood and relatively easy to manipulate.