Glial
Brain Cells, Long in Neurons’ Shadow, Reveal Hidden Powers
Elena Renken
The sting of a paper cut or the
throb of a dog bite is perceived through the skin, where cells react to
mechanical forces and send an electrical message to the brain. These signals
were believed to originate in the naked endings of neurons that extend into the
skin. But a few months ago, scientists came to the surprising realization that
some of the cells essential for sensing this type of pain aren’t neurons at
all. It’s a previously overlooked type of specialized glial
cell that intertwines with nerve endings to form a mesh in the outer
layers of the skin. The information the glial cells send to neurons is what
initiates the “ouch”: When researchers stimulated only the glial cells, mice
pulled back their paws or guarded them while licking or shaking — responses
specific to pain.
This
discovery is only one of many recent findings showing that glia, the motley
collection of cells in the nervous system that aren’t neurons, are far more
important than researchers expected. Glia were long presumed to be housekeepers
that only nourished, protected and swept up after the neurons, whose more
obvious role of channeling electric signals through the brain and body kept
them in the spotlight for centuries. But over the last couple of decades,
research into glia has increased dramatically.
“In the human brain, glial cells
are as abundant as neurons are. Yet we know orders of magnitude less about what
they do than we know about the neurons,” said Shai Shaham, a professor of cell biology at the Rockefeller
University who focuses on glia. As more scientists turn their attention to
glia, findings have been piling up to reveal a family of diverse cells that are
unexpectedly crucial
to vital processes.
It turns out that glia perform a
staggering number of functions. They help process memories.
Some serve as immune
system agents and ward off infection, while some communicate
with neurons. Others are essential to brain development.
Far from being mere valets to neurons, glia often take leading roles in
protecting the brain’s health and directing its development. “Pick any question
in the nervous system, and glial cells will be involved,” Shaham said.
More Than Just ‘Glue’
Glia take many forms to perform
their specialized functions: Some are sheathlike, while others are spindly,
bushy or star-shaped. Many tangle around neurons and form a network so dense
that individual cells are hard to distinguish. To some early observers, they
didn’t even look like cells — they were considered a supportive matrix within
the skull. This prompted the 19th-century researcher Rudolph Virchow to dub
this non-neuronal material “neuroglia,” drawing on the Greek word for glue.
In this
magnified image of brain tissue, neurons (blue) are surrounded by large numbers
of glial cells, including astrocytes (red) and oligodendrocytes (green).
One reason glia were given such
short shrift was that when researchers first began staining nervous system
tissue, their methods revealed the convoluted shapes of neurons but rendered
only select glia visible. Santiago Ramón y Cajal, who is credited
with the discovery of neurons and widely regarded as the founder of
neuroscience, illustrated one subtype of glia but lumped the rest together as
“the third element.” His focus on neurons set the stage for the burgeoning
field of euroscience but shoved the glia behind the curtains.
In addition, some glia are
challenging to study because their fates are so entwined with those of
neurons that it’s hard to learn about them separately. If researchers try to
learn about the glia’s functions by knocking them out and observing the
effects, the neurons they support will die along with them.
But the revolution in cell
biology techniques in recent decades has generated an arsenal of tools offering
greater access to glia, Shaham said. Advances in live imaging, fluorescent
labeling and genetic manipulation are revealing the breadth of glia’s forms and
functions.
Microglia Reveal Their
Versatility
Several cell types are contained
within the umbrella category of glia, with varied functions that are still
coming to light. Oligodendrocytes and Schwann cells wrap around nerve fibers
and insulate them in fatty myelin sheaths, which help to confine the electrical
signals moving through neurons and speed their passage. Astrocytes, with their
complex branching shapes, direct the flow of fluid in the brain, reshape the
synaptic connections between neurons, and recycle the released neurotransmitter
molecules that enable neurons to communicate, among other jobs.
The highly
versatile microglia seem to serve a variety of functions in the brain, such as
removing cellular debris and determining which synapses between neurons are
unnecessary.
But the cells that have been the
subjects of an especially strong spike in interest over the last decade or so
are the ones called microglia.
Microglia were originally defined
in four papers published in 1919 by Pío del Río-Hortega, but the study of
them then stalled for decades, until finally picking up in the 1980s.
Microglia research is now growing exponentially, said Amanda
Sierra, a group leader at the Achucarro Basque Center for Neuroscience. The
work is exposing how microglia respond to brain trauma and other injuries, how
they suppress inflammation, and how they behave in the presence of
neurodegenerative diseases. The cells “really are at the edge between
immunology and neuroscience,” Sierra said.
Guy Brown, a professor of biochemistry at the University of
Cambridge, was first drawn to microglia by their star shapes and dynamic
movements, but it was their behavior that held his attention. In recent years,
microglia have been found to mimic the macrophages of the immune system by
engulfing threats to the brain such as cellular debris and microbes. Microglia
also seem to go after obsolete synapses. “If you live-image them, you can see
them eating neurons,” Brown said.
Some of these active functions
are shared with other types of glia as well. Astrocytes and Schwann cells, for
example, may also prune synaptic connections. But despite the commonalities
among different subsets of glia, researchers are starting to realize that
there’s little to unify glial cells as a group. In fact, in a 2017
article, scientists argued for discarding the general term
“glia” altogether. “They don’t have an enormous amount in common, different
glial cells,” Brown said. “I don’t think there’s much future to glia as a
label.”
Ben Barres, a neuroscientist who
championed glia research and passed away in 2017, considered deeper
investigations of glia essential to the advance of neurobiology as a field.
Others have taken up that cause as well. To them, the historical emphasis on
neurons made sense at one time: “They are the ones who process the information
from the outside world into our memories, our thinking, our processing,” Sierra
said. “They are us.” But now the importance of glia is clear.
Neurons and glia cannot function
independently: Their interactions are vital to the survival of the nervous
system and the memories, thoughts and emotions it generates. But the nature of
their partnership is still mysterious, notes Staci Bilbo, a
professor of psychology and neuroscience at Duke University. Glia are gaining a
reputation for the complexity long attributed to neurons, but it’s still
unclear whether one cell type primarily directs the other. “The big unknown in
the field is: Who is driving the response?” she said.
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