Young brains make connections prodigiously. Thickets of synapses form between neurons early in life, weaving networks of learning and memory.
Before long, however, growing brains need to prune some of their spreading branches. Too many synapses lead to chaos, so at crucial points in brain development, idle synapses are whittled away, clearing the neuronal neighborhood to allow for more precise brain wiring.
This tidying job is undertaken in several ways. One involves the efforts of microglia, specialized immune cells that search and destroy synaptic debris in the brain and throughout the central nervous system. “Glia” comes from the Greek word for glue, and considering their tenacity, the name is apt. Microglia continually survey synapses, leaving the most active ones alone while eliminating the idle ones.
Beth Stevens, an HMS assistant professor of neurology in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, has studied microglia in the brain for nearly a decade, ever since, as a postdoc at Stanford, she realized how little attention had been paid to these agents of synaptic sculpting. Her work investigating the molecular mechanisms shared by the immune and nervous systems places her squarely at the intersection of neurology and immunology.
Microglia serve as immune cells in the brain, performing the same functions of surveillance and removal that other immune players use in the rest of the body to fight invaders. Microglia play defense, too, in at least three ways. First, they rush to sites of injury to mop up intruders and stimulate inflammation in response to damage. Second, they serve as resident phagocytes, cells that remove pathogens and dying cells by engulfing them. And third, they have surface receptors for complement proteins, the immune molecules that tag pathogens and cellular debris with a message that tells microglia to eat the intruders. Stevens and her team discovered that, in the healthy brain, complement proteins tag extraneous synapses for removal by microglia.
Changes in microglial activity may have a role in disease. In schizophrenia, which, coincidentally, may begin to manifest around the time of normal synaptic pruning during teenage years, brain studies show sparse connections between neurons. In neurodegenerative diseases such as Alzheimer’s, synapses almost vanish in areas of the brain devoted to memory.
Stevens hypothesizes that the same pathways that allow synapses to get pruned during normal development get reactivated to drive synapse loss in neurodegenerative diseases. “These diseases,” she says, “are so different in their genetics and in their age of onset, yet they share the features of synapse loss, microglial activity, and the abnormal presence of complement proteins.”
“This is like having a good thing go awry,” Stevens adds. “A normal developmental mechanism is tipped: Too much of a good thing is not a good thing. But it makes sense to me that your brain might use some of the same mechanisms twice.”
Stevens does not suggest that taming microglia could solve neurological diseases by itself. But the cells may represent a target pathway for diagnosis, particularly in Alzheimer’s disease, because synaptic loss occurs years before people begin to show signs of deteriorating memory or weakening cognitive function.
For diseases that seem as densely complex as the brain itself, understanding the interplay between microglia, immune cells, and synaptic connections may offer a path through the thickets.
Photo: Courtesy of Beth Stevens