ARTICLE IN BRIEF
Neuroscientist Beth Stevens, PhD, the recipient of a MacArthur Foundation “genius” grant, discusses her research on the role of microglia and complement in synaptic pruning.
In October, Beth Stevens, PhD, an assistant professor of neurology at Harvard Medical School and the F.M. Kirby Neurobiology Center at Boston Children's Hospital, was named one of the 24 recipients of the MacArthur Foundation's prestigious fellowship. The program awards a “no strings attached” grant of $625,000, paid out in quarterly installments over five years, to exceptional individuals in disciplines such as the arts, education, sociology, biology, chemistry, engineering, and neuroscience.
Dr. Stevens' research on microglial cells has prompted a sea change in the way neurologists and neuroscientists think about these cells. Once thought to serve primarily immunological functions in the brain, Dr. Stevens discovered that microglia are also responsible for pruning synapses during brain development. She and her colleagues also identified immune proteins that “tag” synaptic cells for removal by microglia. Her work has implications for understanding diseases such as autism, schizophrenia, Alzheimer's, and Huntington's. Dr. Stevens spoke with Neurology Today about these discoveries, the colleagues who inspired and propelled her research, and her reaction to receiving the prestigious MacArthur “genius” grant.
Dr. Stevens was in her office working on a grant application when she received the call about the MacArthur award. “It seemed surreal because it was such a surprise,” she said. “You have no idea you're being considered for something like this. And then I had to keep it quiet for a few weeks after that, so it was a surreal experience until it was officially announced.”
But she was immensely grateful. She sees the award as a way to push her lab's current lines of investigation — delving further into the mechanisms of synaptic pruning in normal brain development; understanding the role dysfunction in the pruning pathway might play in autism and schizophrenia; and investigating whether this same pathway becomes reactivated in neurodegenerative diseases — forward into bolder territory.
Humans are born with an excess of synapses in the brain — roughly twice as many as are needed for optimal brain function, she explained. But early in development, these synapses are trimmed away. The important synaptic connections are strengthened, while weak or unwanted synapses are eliminated, resulting in a brain where only the most efficient neuronal connections remain.
Until recently, microglia — the brain's immune cells — were not thought to play a role in this pruning process. But Dr. Stevens' research has shown that, in fact, these cells engulf or “eat” extra synapses that have been tagged for elimination.
The 2015 MacArthur grantee has worked with glial cell types for nearly her entire scientific career, beginning with her stint as a research assistant in the lab of R. Douglas Fields, PhD, at the National Institutes of Health (NIH), after undergraduate school.
“Compared with neurons, there was much less known about the functions and roles of glia,” she said, “both in the normal brain and in disease.” She found herself particularly fascinated by the role of glia during brain development, “when the brain is wiring up.”
But for a long time, she didn't pay much attention to microglia. “They're an immune cell, and they're the only type of glial cell not born in the brain. They're derived from an immune progenitor cell that was long thought to come in after birth.” (A number of imaging studies in 2010 would later prove that was not the case, that “these cells actually come into the brain quite early,” Dr. Stevens said.) But in her postgraduate work, Dr. Stevens would come to find this previously dismissed cell type captivating.
SYNAPTIC PRUNING IN THE DEVELOPING BRAIN
After obtaining her PhD from the University of Maryland in 2003, Dr. Stevens moved to the lab of Ben A. Barres, MD, PhD, a professor of neurobiology, developmental biology, neurology, and ophthalmology at Stanford. There, the researchers made a discovery that would pave the way for Dr. Stevens' later work. They found that C1q, the initiating protein in the classical complement cascade, which “tags” cells or debris for engulfment or removal by immune cells, is expressed in postnatal neurons, binding to synapses in the developing visual system. This suggested to the researchers that C1q might be doing the same thing in the brain as it does in the immune system, tagging unwanted synapses for removal.
Using mouse models, they showed that removing C1q or the downstream complement protein C3 would result in defects in synapse elimination in the central nervous system. Furthermore, they found that in a mouse model of glaucoma, this complement protein became up-regulated in the adult retina early in the disease, suggesting that this process of synapse elimination might become aberrantly reactivated in neurodegenerative disease.
When Dr. Stevens started her own lab at Harvard and Boston Children's Hospital in 2008, she resolved to investigate this crucial process of synaptic pruning further. That led her to microglia. “In the immune system, [complement] molecules are basically ‘eat me’ signals,” she explained. Given microglia's immunological function in the brain, working to reduce inflammation and eliminate debris, Dr. Stevens wondered whether these cells could be working with complement to engage in synaptic pruning.
A postdoctoral fellow in Dr. Stevens' lab, Dorothy Schafer, PhD, set about designing experiments by which they could test this hypothesis. Using the mouse visual system as their model, they labeled synapses with one color of fluorescent dye and microglia with another. They were able to observe, using high-resolution imaging and three-dimensional reconstruction, that microglia were, indeed, engulfing or “eating” extra synapses during brain development.
That work, published in Neuron in May 2012, was widely praised in the neuroscience community for bringing about an entirely new understanding of the role of microglia.
The next step, Dr. Stevens said, is to further understand how and why certain synapses are tagged and targeted for elimination.
SYNAPTIC PRUNING IN DISEASE
Armed with the understanding that microglia play an important role in synaptic pruning during normal brain development, Dr. Stevens and her colleagues wanted to examine whether microglia might also be implicated in disease. Since brain disorders such as schizophrenia and autism have been linked with defects in synaptic connectivity, could microglia be implicated in those diseases? And, in the adult brain, could that same pruning process become reactivated to produce the synaptic loss seen in, for example, Alzheimer's and Huntington's disease?
In the context of aging, synaptic pruning “is not a good thing,” Dr. Stevens said. “You don't want to lose all of your [synaptic] connections, especially too soon in life. It has been a big mystery in terms of what makes those synapses vulnerable or what actually contributes to that synapse loss.”
Dr. Stevens' lab, in collaboration with Cynthia A. Lemere, PhD, an associate professor of neurology at Harvard Medical School, and her colleagues at Harvard and Brigham and Women's Hospital, have begun to investigate that question. In September, they published a paper in the Journal of Neuroscience showing that mice lacking complement C3 — one of the “eat me” signals that tags synaptic cells for elimination — do not have the same age-related synapse and neuron loss in the hippocampus as wild-type mice. What's more, the aged C3-deficient mice showed significantly better cognition and less anxiety than wild-type mice.
“Not only were fewer synapses [lost], it seemed like blocking complement also had a protective function in terms of memory and plasticity in the brain,” Dr. Stevens said. “We're very excited about the idea.”
Microglia were not studied in this model, Dr. Stevens noted, but “microglia may very well be part of that [process] as well.”
THE MACARTHUR AWARD
Dr. Stevens said she is excited to take the research further. She's also happy that the award has brought attention to an under-recognized but very promising area of neuroscience. “It allows us to move some of [our] higher-risk projects to the front-burner.”
These riskier projects are so rarely funded in the current research climate, she said. Now, the MacArthur award “enables us to continue to go for these exciting questions we really want to go for, even if it's early days.”
And on a more personal note, Dr. Stevens said she hopes the grant will allow her more of that ever-elusive work-life balance. The MacArthur fellowship, after all, is not just a prestigious line on a resumé. It's one less grant application that needs to be filled out.
Dr. Beth Stevens, 2015 MacArthur Fellow, Discusses Her Research on Microglia
NEUROLOGY IN THE NEWS: In October, Beth Stevens, PhD, an assistant professor of neurology at Harvard Medical School and the F.M. Kirby Neurobiology Center at Boston Children's Hospital, was named one of the recipients of the MacArthur Foundation's prestigious fellowship. Her research on microglial cells has prompted a sea change in the way neurologists and neuroscientists think about these cells, and has implications for understanding diseases such as autism, schizophrenia, Alzheimer's, and Huntington's. As part of the Neurology Today podcast series, Neurology in the News, Dr. Stevens spoke with us about some of her groundbreaking research on the role of microglia and complement in the synaptic pruning process. Listen to the podcast at http://bit.ly/Stevens-podcast.