Microglia’s role in brain development: A neuroscientist looks back

The journal Neuron, celebrating its 25th anniversary, recently picked one influential neuroscience paper from each year of the publication. In this two-part series, we feature the two Boston Children’s Hospital’s scientists who made the cut. The Q&A below is adapted with kind permission from Cell Press.

Microglial cell with synapses
CAUGHT IN THE ACT: This microglial cell is from the lateral geniculate nucleus, which receives visual input from the eyes. The red and blue are synapses that it has engulfed. (Blue synapses represent inputs from the same-side eye; red, the opposite-side eye.)

In 2012, Beth Stevens, PhD, and colleagues provided a new understanding of how glial cells shape healthy brain development. Glia were once thought to be merely nerve “glue” (the meaning of “glia” from the Greek), serving only to protect and support neurons. “In the field of neuroscience, glia have often been ignored,” Stevens told Vector last year.

No longer. Stevens’s 2012 paper documented that microglia—glial cells best known for their immune function—are no passive bystanders. They get rid of excess connections, or synapses, in the developing brain the same way they’d dispatch an invading pathogen—by eating them.

The findings have spawned new directions in research that could ultimately change how scientists think about disorders ranging from autism to amyotrophic lateral sclerosis (ALS) to Alzheimer’s.

What stimulated your interest in neuroscience?

When I was a graduate student, the notion that glial cells are active participants in the brain was just beginning to be appreciated. There were glial biologists and there were neurobiologists, and typically these two fields did not mix. I was fortunate to have had two excellent and passionate mentors who gave me many opportunities to learn and explore this new space.

I became fascinated by glia and the fact that we knew so little about a cell type that makes up more than half of the brain. This set me on an exciting path that gets more interesting with every step.

What influences have shaped your research?

A collaborative and diverse scientific environment. Our work has put us at the exciting interface between the nervous and immune systems. I have learned so much from interacting with my immunologist colleagues and those in other fields who continually offer different perspectives and important tools.

How has the field developed since the publication of your paper?

Beth Stevens
STEVENS

Interest in microglia is building momentum across many disciplines. Developmental neurobiologists have long ignored these cells, and until very recently, microglia were primarily studied in the context of disease and neuroinflammation.

Our finding that microglia are key players in synaptic pruning was one of the first of several recent papers implicating microglia in synapse development and plasticity (the ability of neurons to form new connections). The recent fate-mapping study by Miriam Merad’s lab at the Mount Sinai Immunology Institute was a game-changer. Microglia were long thought to enter the brain after birth; we now know that the majority derive from progenitors that migrate into the brain very early in embryonic development. This puts microglia at the right place at the right time to influence a wide range of developmental processes needed to build and wire the brain.

There is also growing interest in the potential link between microglia dysfunction and neurodevelopmental disorders, such as Rett syndrome and autism.

What are the next big questions?

The next big step is understanding how microglia are talking to neurons—and synapses—in the healthy brain. There is likely to be an active bi-directional dialogue between microglia and neurons, but we know remarkably little about the signals. Microglia have an array of surface receptors that could be activated by neuronal signals. At the same time, microglia could release growth factors, cytokines, and novel signals that could regulate neuronal and synaptic function.

Our paper identified the complement system as one mechanism underlying microglia engulfment of synapses. Fractalkine signaling is another. One of the challenges in identifying new signals is that microglia, unlike neurons and astrocytes, cannot be easily studied in culture, out of their natural environment. I think it will be critical to develop new culture systems and functional assays.

This is an exciting time to be studying microglia. And with the development of new tools and functional assays, we are finally positioned to make rapid progress in understanding their function in the healthy brain.

Do you have any advice for scientists that are just starting out?

Choose a great mentor. Choose an important question. Choose a good model system. Surround yourself with brilliant and supportive colleagues. And try not to let the current funding climate alter your goal to do innovative and excellent science.

See part 2, Neuronal migration and a well-configured cortex.