Vol 457|5 February 2009

Q&A
NEUROSCIENCE

Glia — more than just brain glue

Nicola J. Allen and Ben A. Barres
Glia make up most of the cells in the brain, yet until recently they were believed to have only a
passive, supporting role. It is now becoming increasingly clear that these cells have other functions:
they make crucial contributions to the formation, operation and adaptation of neural circuitry.

How do glia differ from has roughly 65% of these cells;

neurons? the human brain has about 90%;
The defining characteristic and the elephant brain consists of
of a neuron is its ability some 97% glia. As animals have
to transmit rapid electrical evolved, glia have become not only
signals in the form of action more diverse and specialized, but
Fc`^f[\e[ifZpk\
potentials. All other E\life niXgjdp\c`eXifle[
also essential: without them neu-
neural cells that lack this dlck`gc\Xofej rons die. Furthermore, astrocytes
property are catego- in the human cerebral cortex are
rized into a broad Gi\jpeXgk`Z GfjkjpeXgk`Z much more complex than those of
class termed glia. k\id`eXc k\id`eXc other mammals, and are thought
Neurons are arranged to be involved in information
in networks (circuits), 8ofe processing.
and communicate with each
other via specialized intercellular So what exactly do glia do?
D`Zif^c`X
f^c`X 8jkifZpk\gifZ\jj
adhesion sites called synapses. \ej_\Xk_j
Lots of things. The traditional
Neuronal signalling involves the k_\jpeXgj\ 8jkifZpk\
8jki view has been that glia look after
propagation of an action poten- neurons and maintain their proper
tial down a neuron’s axonal pro- functioning, having a somewhat
cess to a presynaptic terminal; passive role themselves. Estab-
the depolarization of the terminal lished functions of glia include
and release of neurotransmitters; supporting neurotransmission,
binding of the released neuro- 9cff[m\jj\c maintaining ionic balance in the
transmitters to receptors on the extracellular space, and insulat-
postsynaptic membrane of another ing axons to speed up electrical
neuron; and the sub sequent 8jkifZpk\\e[$]\\k communication. But emerging
depolarization of this second neu- niXgXifle[k_\ research suggests that glia, par-
Ycff[m\jj\c
ron, propagating the signal further. ticularly astrocytes, also have
Glia do not fire action potentials, an active role in brain function
but instead surround and ensheath and information processing —
Figure 1 | Glia–neuron interactions. Different types of glia interact with
neuronal cell bodies, axons and both during development and in
neurons and the surrounding blood vessels. Oligodendrocytes wrap myelin
synapses throughout the nervous around axons to speed up neuronal transmission. Astrocytes extend
adulthood.
system. processes that ensheath blood vessels and synapses. Microglia keep the
brain under surveillance for damage or infection. What is the specific function
Are all glia the same? of microglia?
No. On the basis of morphology, These resident immune cells
function and location in the nervous system, brain from the blood circulation early in an of the nervous system survey the brain
there are several classes of glia. In mammals, organism’s development. for damage and infection, engulfing dead
for example, glia are classified as microglia, cells and debris. Microglia have also been
astrocytes and the related Schwann cells and What is known about the evolution implicated in synaptic remodelling during
oligodendrocytes (Fig. 1). of glia? the development of the nervous system,
Glia are evolutionarily conserved, being present when they are proposed to remove inappro-
Where do they originate from? in one form or another in most species priate synaptic connections through the
Glia and neurons mainly share a common examined, from the simplest invertebrates to process of phagocytosis. More over, they
origin — precursor cells derived from the embry- humans. The proportion of glia seems to be are activated in many neurodegenera-
onic germ layer known as the neuroectoderm. correlated with an animal’s size: the tiny nema- tive diseases, but whether they are helpful
A notable exception is microglia, which tode worm has only a few glia; some 25% of the or harmful in these conditions is a matter
are part of the immune system and enter the fruitfly brain consists of glia; the mouse brain of debate.
675
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NEWS & VIEWS Q&A NATURE|Vol 457|5 February 2009

terminating the action of neurotransmitters

secreted by neurons and for mediating their
recycling back to neurons in a process known
as the glutamate–glutamine cycle.

Are all astrocytes the same?

No. These cells are broadly divided into two
groups — protoplasmic astrocytes found in the
brain’s grey matter and fibrous astrocytes of
the white matter. Protoplasmic astrocytes are
intimately associated with neuronal cell bodies
and synapses, whereas fibrous astrocytes are
associated with neuronal axons. Furthermore,
types of protoplasmic astrocyte differ between
the various regions of grey matter; even within
a single brain region, neighbouring astrocytes
are probably different. This is not surprising,
because, if they are to fulfil different functions,
these cells must adapt to specific brain regions.
Exact functional differences between the
various types of astrocyte remain elusive.

Do astrocytes talk to each other?

Yes. They communicate with each other
through waves of calcium ions, propagating
information over large distances. Stimulation
of one astrocyte can cause a calcium response
in a subset of neighbouring astrocytes, with
no response in other subsets, indicating the
Figure 2 | An astrocyte in action. This micrograph shows a protoplasmic astrocyte (green) enveloping presence of distinct networks of astrocytes
the cell body and the processes of a neuron (red). The bushy nature of astrocytes, evident in this image, organized in a mosaic pattern. Although indi-
allows them to form distinct domains in the brain. Scale bar, 10 μm. (Image courtesy of M. Ellisman vidual astrocytes occupy distinct domains, and
and E. Bushong, Univ. California, San Diego.) cellular projections from neighbouring astro-
cytes do not overlap in the adult brain, these
cells are linked together by structures in their
What do oligodendrocytes and connections of neighbouring neurons, and cell bodies called gap junctions.
Schwann cells do? remove excess neurotransmitter molecules
In vertebrates, these cells are essential for rapid from the extracellular space, allowing discrete Do they communicate with
electrical communication between neurons and precise encoding of synaptic signals and neurons too?
and their targets. Oligodendrocytes (in the neurotransmission. Recently, unexpected Bidirectional communication does indeed
central nervous system) and Schwann cells roles for astrocytes have been identified — occur between neurons and astrocytes. Indi-
(in the peripheral nervous system) produce a they seem to be involved in the formation of vidual astrocytes can make contact with
lipid-rich membrane called myelin, which synapses and in modulating synaptic func- and ensheath thousands of synapses formed
enwraps axons, thereby speeding up the con- tion through bidirectional communication between many different neurons. This means
duction of electrical impulses. In the absence with neurons. For this reason, the next few that synapses don’t consist of just a pre- and
of myelin, the conduction velocity of an action questions are dedicated to this, currently the postsynaptic neuronal element, but that many
potential is directly proportional to the diam- ‘hottest’, type of glia. also have an astrocytic projection that envelops
eter of the axon. This means that the final the synapse. This close spatial relationship has
size of an animal would be limited by the fact How exactly do astrocytes contribute led to the term tripartite synapse, to acknowl-
that its axons would eventually become pro- to homeostasis in the brain? edge the astrocyte’s contribution (Fig. 3). The
hibitively large. The evolution of myelin has Astrocytes control blood flow through their synaptic localization of astrocytes means they
allowed animal size to increase without a cor- numerous fine processes, which form close are ideally placed to monitor — and respond
responding increase in axon diameter, enabling associations with both blood vessels and neu- to — synaptic activity. Moreover, astrocytes
rapid thought and action. Besides, myelination rons. In response to enhanced neuronal activ- possess many of the same neurotransmitter
induces clustering of ion channels, thereby fur- ity, astrocytes signal to blood vessels about the receptors as neurons, and neurotransmitter
ther enhancing conduction velocity. ‘Demyelin- need for regional increases in blood flow, which release by neurons activates calcium-based
ation’ — due to damage to oligodendrocytes results in enhanced delivery of oxygen and signalling cascades in astrocytes. Astrocytes
and Schwann cells — leads to various diseases, glucose to the active brain region. Analysis of then release neuroactive substances, signal-
including multiple sclerosis and hereditary such changes in blood flow forms the basis of the ling back to neurons to form a feedback loop.
sensorimotor neuropathy. study of brain function by functional magnetic The different types of molecule secreted by
resonance imaging (fMRI). Besides regulating astrocytes can either inhibit or enhance overall
And what about astrocytes? blood flow, astrocytes ferry glucose and oxy- levels of neuronal activity.
Put simply, astrocytes allow neurons to function gen from blood to neurons. It is hypothesized
(Fig. 2). They contribute to homeostasis in that they convert glucose into lactate. Lactate is Do any types of glia receive direct
the brain by providing neurons with energy then exported to neurons, where it is converted neuronal input ?
and substrates for neurotransmission. They to pyruvate to produce the cell’s energy mol- Possibly. Cells expressing the proteoglycan
act as physical barriers between the synaptic ecule ATP. Astrocytes are also responsible for NG2, which are thought to be oligodendrocyte
676
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NATURE|Vol 457|5 February 2009 NEWS & VIEWS Q&A

precursor cells, have been shown to receive Figure 3 | A tripartite synapse.

direct synaptic signals from neurons, some of Astrocytes express many of
them even firing action-potential-like signals Gi\jpeXgk`Z GfjkjpeXgk`Z the same receptors as neurons.
in response. The significance of this inner- k\id`eXc k\id`eXc When neurotransmitters are
vation is not known. Does it influence the released from the presynaptic
terminal of a neuron, astrocytic
decision of NG2-expressing cells to become E\life E\life
receptors are thought to be
oligodendrocytes, or even neurons? And could ( )
activated, leading to a rise in
it result in the recruitment of NG2 cells into calcium ions in the astrocyte
specific neural networks? and the release of various active
substances, such as ATP, which
What is the role of glia in embryonic I\Z\gkfi act back on neurons to either
brain development? inhibit or enhance neuronal
Some glia give rise to neurons, and others activity. Astrocytes also release
guide neurons to their correct location in the proteins, which control synapse
formation, regulate presynaptic
nervous system — so they are essential for
function and modulate the
brain development. During embryonic devel- response of the postsynaptic
opment, a specialized type of glia called radial neuron to neurotransmitters.
glia divide to form neural progenitor cells. JlYjkXeZ\
Moreover, the long processes of radial glia span i\c\Xj\
the cortex, providing tracks along which newly 8jkifZpk\
generated neurons migrate to reach their cor- gifZ\jj
rect location. Once all neurons are in place,
:XcZ`ldi`j\
the processes of radial glia degenerate and
they form cortical astrocytes. Besides guiding
neurons to their correct location, glia provide
a scaffold along which axons grow. They per-
form this pathfinding function through both loss of oligodendrocytes and myelin has been crucial are these networks, and can they pro-
attractive and repulsive interactions with reported in clinical depression. cess information in the absence of neurons?
receptors present on the axon. How do glia contribute to disease, and might
What experimental models are used they be a potential target for drugs?
And how do they contribute to the to study glia?
formation of neural networks? Studying the role of glia in nervous-system Why the resurgence of interest?
They do so by aiding synapse formation and function is difficult because, in most organ- A historical difficulty with studying glia has been
possibly synapse elimination. Astrocytes, for isms, glia are essential for neuronal survival the ‘neuro-centric’ view of the brain, implicit
instance, induce synapse formation in several and so their removal causes neuronal death. in the name of the discipline: neuroscience.
classes of neuron, both by direct contact with Therefore, much of what we know about glia Fortunately, there is a growing appreciation of
neurons and by secreting factors that regulate has come from studies of isolated mammalian the importance of other cell types in the nerv-
synapse formation as well as pre- and post- glia maintained in vitro. Although such analy- ous system and their symbiotic relationship
synaptic functions. But such actions are not sis is useful and has taught us much about the with neurons, with no single cell type now
restricted to astrocytes. Oligodendrocytes basic properties of glia, it cannot tell us how being viewed as more important than the
and Schwann cells also induce synapse for- glia interact with other cell types. Electrophys- others. By examining how all of these cells
mation between neurons. It is not clear how iological and calcium imaging studies using work together, neurobiologists hope to make
such glial signals act: do they provide a per- mammalian brain slices have begun to pro- more rapid progress in understanding how the
missive environment for synapse formation vide insight into both glia–neuron interaction nervous system forms, functions, adapts and
at sites predetermined by neurons, or do they and the role of glia in the activity of neuronal can be repaired. ■
actively instruct neurons where to form syn- networks. Also, with advances in live imaging Nicola J. Allen and Ben A. Barres are in the
apses? As mentioned previously, microglia are techniques, such as in vivo two-photon micro- Department of Neurobiology, Stanford University
also implicated in the removal of inappropri- scopy, glial activity and its correlation with School of Medicine, Stanford, California
ate synaptic connections and so in fine-scale blood flow and behaviour can be monitored 94305-5125, USA.
‘sculpting’ of neuronal networks. in living animals. Studying small model organ- e-mails: njallen@stanford.edu;
isms, including worms, fruitflies and fish, is barres@stanford.edu
Do glia play a part in disease? another powerful approach that has allowed
Glia can be a help or a hindrance in disorders dissection of the role of glia in nervous-system FURTHER READING
Allen, N. J. & Barres, B. A. Signaling between glia
of the nervous system, and their malfunction function by means of genetic engineering. and neurons: focus on synaptic plasticity. Curr. Opin.
has been implicated in many such diseases. For Neurobiol. 15, 542–548 (2005).
example, following spinal-cord injury, astro- So what is left to learn about them? Barres, B. A. The mystery and magic of glia: a
perspective on their roles in health and disease.
cytes form a glial scar that acts as a barrier to Lots! Although the recent resurgence of Neuron 60, 430–440 (2008).
the regeneration of damaged axons. Moreover, interest in glia has led to many exciting and Freeman, M. R. & Doherty, J. Glial cell biology in
in the neurodegenerative disease amyotrophic unexpected discoveries about the roles of these Drosophila and vertebrates. Trends Neurosci. 29,
82–90 (2006).
lateral sclerosis, astrocytes secrete a toxic fac- cells in the nervous system, such findings are Haydon, P. G. & Carmignoto, G. Astrocyte control of
tor that kills motor neurons — those involved almost certainly just the tip of the iceberg, synaptic transmission and neurovascular coupling.
in muscle function. And astrocytes can some- and there are many outstanding questions. Physiol. Rev. 86, 1009–1031 (2006).
Kettenmann, H. & Ransom, B. R. (eds) Neuroglia
times become cancerous, giving rise to brain How exactly do glia participate in the forma- 2nd edn (Oxford Univ. Press, 2005).
tumours called gliomas. Also, as mentioned tion and functioning of neuronal networks? Nave, K.-A. & Trapp, B. D. Axon–glial signaling and the
earlier, oligodendrocytes are the target of an Do glia have essential functions beyond sup- glial support of axon function. Annu. Rev. Neurosci. 31,
535–561 (2008).
autoimmune attack in multiple sclerosis that porting and interacting with neurons? What Wang, D. D. & Bordey, A. The astrocyte odyssey.
causes demyelination. Unexpectedly, profound is the extent of astrocytic networks? How Prog. Neurobiol. 86, 342–367 (2008).

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