A baby's brain has a lot of work to do, growing more neurons and connections.
Later, a growing child's brain begins to pare down these connections until it develops into the streamlined brain of an adult.
Now researchers at the Stanford University School of Medicine have discovered the sculptor behind that paring process: the immune system.
The value of this discovery goes beyond understanding how connections are weeded out in a normal, developing brain. The finding could also help explain some neurodegenerative disorders - such as glaucoma, Alzheimer's disease and multiple sclerosis - that result from the loss of too many neuronal connections, which are known as synapses.
The advance, which has implications for drugs that could halt or reverse such conditions, will be published in the Dec. 14 issue of the journal Cell.
It was widely known that synapse elimination occurs during normal development of a child's brain, but until now, no one knew how certain synapses were flagged for removal. "We have identified the long-mysterious mechanism by which excess synapses are sculpted away in the developing brain," said the study's senior author, Ben Barres, MD, PhD, professor of neurobiology.
Barres' team found that the brain-sculpting process was controlled by a component of the immune system known as the classical complement cascade.
The complement cascade is one part of the multipronged attack the immune system launches throughout the body when it detects a foreign invader. Consisting of more than 20 small proteins that normally circulate in the blood in their inactive forms, the complement system is triggered into action by an invading parasite. The first activated protein activates a second one, which in turn activates a third, continuing down the line in a domino effect, ultimately yielding a membrane-attack response that kills cells.
Barres' team produced the first proof that the complement system also plays a role in the brain by showing that complement proteins bind to unwanted synapses, targeting them for elimination. Future studies will determine how the synapses are marked for death.
When children reach the age of 10, synapse elimination normally shuts down. But the researchers found that this elimination process becomes reactivated very early in glaucoma, a neurodegenerative disease that is a major cause of blindness. They found that the earliest known sign in glaucoma was the complement cascade becoming active at synapses, followed by massive synapse loss. Only much later did the neurons die, which is the hallmark of neurodegenerative diseases.
"This is interesting, as these complement proteins are known to be drastically up-regulated in nearly every neurodegenerative disease process that has been examined," said Barres. Up-regulation is the process by which a cell increases the amount of a molecule, such as a protein, in response to a change in its environment. Alzheimer's disease, which involves massive synapse loss, has a hundredfold up-regulation of complement proteins, he said.
First author Beth Stevens, PhD, a postdoctoral scholar in Barres' lab, said these findings in glaucoma made the team wonder if the same synapse-elimination process is restarted in other neurodegenerative diseases. "It's an exciting thought, as this would be the earliest sign of disease so far," she said.