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Neuroscience- Settling the Great Glia Debate

Neuroscience- Settling the Great Glia Debate

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H
alfway through a satellite meeting at the Feeration of European Neurosciences conference in Amsteram in
July, researcher Ken McCarthy takes the stage to give
his presentation. He sports a black shirt an jeans, an his strong
cheekbones, shock of white hair an tanne skin give him the
look of a film star. But he oesn’t have the confience to match. “I
find this a little bit daunting,” he says, as he organizes his slides.
McCarthy, a geneticist at the University of North Carolina School
of Meicine in Chapel Hill, is about to fan the flames of a ebate
about whether glia, the largest contingent of non-neuronal cells in
the brain, are important in transmitting electrical messages. For
many years, neurons were thought to be alone in executing thistask, an glia were consigne to a supporting role — regulatinga neuron’s environment, helping it to grow, an even proviing
physical scaffolding (glia is Greek for ‘glue’).
In the past couple of ecaes, however, this picture has beenchanging. Some glia, known as astrocytes, have thousans of bushy tenrils that nestle close to the active junctions between
neurons — the synapses (see 'Neural threesome'). Here they seem
to listen in on neuronal activity and, in turn, to influence it. Stud-ies show that chemical transmitters released by neurons cause an
increase in the levels of calcium insie astrocytes, spurring themto release transmitters of their own. These can enhance or mute
the signalling between neurons, or influence the strength of their
connections over time. Moreover, astrocytes activate at one syn-apse might communicate with other synapses an astrocytes with
which they make contact.
The consequences of this ‘gliotransmission’ coul be profoun.
The human brain contains roughly equal numbers of glia an
neurons (about 85 billion of each), an any given astrocyte can
make as many as 30,000 connections with cells aroun it. If glia are
involve in signalling, processing in the brain turns out to be an
orer of magnitue more complex than previously expecte, says
Do the illionsof non-neuronalcells in the rainsend essages of their own?
Settling the greaglia debate 
By Kerri Smith
Astrocytes (stained green) form rich networks in the brain, which may increase the complexity of neural processing.
   N .   K   E   D   E   R   S   H   A   /   S   P   L
160 | NATURE | VOL 468 | 11 NOVEmbER 2010
© 20 Macmillan Publishers Limited. All rights reserved10
 
Anrea Volterra, who stuies astrocytes at the University of 
Lausanne in Switzerlan. Neuroscientists, who have long focuse
on the neuron, he says, woul “have to revise everything”. In the
past year or so, several papers have highlighte the urgency of 
this revision.But the research that McCarthy is about to discuss could put a
stop to the enthusiasm. “I’m presenting work from genetic stuies
that fly in the face of gliotransmission,” he begins. Most stuiesso far have investigate astrocytes culture in ishes, an bom-
bare them with calcium to elicit an effect. It has long been
suggeste, however, that these methos aren’t specific enough toastrocytes, an might be affecting neurons as well. What is neee
is a way to target astrocytes alone. So McCarthy has evelope
genetically engineere mice in which astrocytes can't signal nor-
mally. The mutations seem to have no effect on neuronal trans-
mission in the brain.
His groups fining coul come as a relief to some. Given the
enormous neural complexity that gliotransmission woul imply,“people on’t want astrocytes to be involve”, says Phil Hayon, a
neuroscientist who stuies glia at Tufts University in Boston, Mas-
sachusetts. But many, incluing most at the Amsteram meeting,have built their careers on gliotransmission. In aition to theireffects on the ay-to-ay functioning of the central nervous sys-tem, glia have opene new avenues of research into sleep, as well
as psychiatric an neurological isease. Now, researchers are being
force to prove McCarthy wrong, or re-evaluate the funamentalprecepts upon which the fiel was built. Davi Attwell, a neuro-
scientist at University College Lonon, says
that emotions in the community are running
high. “If someone comes along an says that
everything you’ve one is wrong, it’s like you’ve
waste your life,” he says. “It’s become quite a
polarized field, just in the last year or two.”
The bomb
Gliotransmission has ha plenty of supportrecently. In January this year, a group le by 
Dmitri Rusakov at University College Lonon an Stéphane Olietat the University of Boreaux in France publishe results
1
suggest-ing that the chemical d-serine, release from astrocytes, activates
a particular receptor — the NMDAR, or
-methyl-d-aspartate
receptor — on the surface of neurons, influencing their behaviour.
Communication through NMDARs is thought to be importantin learning an memory, because it can help to enhance chatter
between synapses and help memories to form.And in September, a team led by Justin Lee at the Korea Insti-
tute of Science an Technology in Seoul foun evience
2
that
astrocytes in the cerebellum release the neurotransmitter GABA(γ-aminobutyric aci). However, unlike the work of most groups,which suggests that astrocytes release chemicals package withintiny bubbles calle vesicles, Lee’s experiments imply that the cells
are transmitting the chemicals irectly through an ion channel
in their membranes. When the researchers blocked the channel,
calle Bestrophin-1, GABA levels went own, suggesting that glia
release GABA through this outlet.
But there have been concerns about experimental techniques.
In these experiments, and many before them, investigators have
trie to inuce astrocyte signalling in petri ishes by pipet-
ting calcium into iniviual cells an watching what happens.This approach is “like an atom bomb” going off in the cell, says
McCarthy. Under natural conditions, the level of calcium would
increase much more slowly, an McCarthy is concerne that
pumping a cell full of calcium could make it behave strangely —
perhaps forcing it to prouce transmitters, or even preventingit from releasing anything. McCarthy hope to unpick the role
of glia in the brain using his genetically engineere mice. “We
thought this would definitively show gliotransmission,” he says.
Instea, it totally crushe expectations. The team, le by 
McCarthy’s postoc, Cenra Agulhon, stuie two mouse lines:
one in which calcium signalling in astrocytes ha been given aboost, an another in which it ha been completely obliterate.But neither change mae any ifference to how nearby neuronswere going about their business. McCarthy an his group wereforce to conclue that astrocytes couln’t possibly be releasingchemicals to signal to neurons. They publishe their results in
Science
in March this year
3
.
At the meeting in Amsteram, McCarthy iscusses his group’s
ongoing search for a behavioural effect that they coul attribute
to their wonky astrocytes. Again, no ice. “I woul love to be able
to show you that, but I can’t,” McCarthy says, ami murmurs of 
disbelief from the audience.
But some researchers have problems with his moel. “The way 
he does it bothers me,” says Richard Robitaille, a glia biologist at
the University of Montreal in Canaa. Measuring the effect of 
astrocytes will require more subtle experimental approaches, hesays. Haydon agrees that it would be better to use more sensitivemethods. He pictures astrocyte responses to stimuli as a narrow
bell curve: if you blast them with something, they o nothing; if 
you on’t stimulate them at all, they o nothing. But ‘talk’ to themusing a low level of physiologically relevant stimulation an they 
shoul talk back. In McCarthy’s mice, says Hayon, taking out
the activity of all astrocytes probably changes
so much — uring brain evelopment, an
throughout life — that it is impossible to tell
what the normal job of glia might be an how
the brain compensates for their absence. The
mice are thus subject to the same ‘atom bomb
criticism levelled at cell-culture studies.Part of the problem could be cultural. “The
entire fiel has been traine in neurocentric
labs, an everyboy has so far believe thatastrocytes work like neurons,” says Maiken Neergaar, a glial
biologist at the University of Rochester in New York. “But astro-cytes function totally ifferently. They use a ifferent language.They use a ifferent way of getting input an output.” They may 
also work on a totally ifferent timescale from neurons, says Rusa-
kov. Their responses, he says, can be three orers of magnitue
slower. As a consequence, common techniques for measuring
neuronal responses won’t work on astrocytes. Methods for imag-ing calcium in cells aren’t good at measuring slow fluctuations or
increases in the outer reaches of astrocytes, partly because calcium
dyes simply don’t penetrate there.
At his lab at the University of California, Los Angeles, Baljit
Khakh has been eveloping a technique that can etect calcium inthe previously inaccessible branches of astrocytes
4
. His team took an existing protein that is known to sense calcium, an moifieit so that it coul be targete to cell membranes, where research-
ers suspect much of the calcium signalling might be going on.
His work shows that a calcium increase in
the main boy of the astrocyte in’t neces-sarily cause a corresponing rise in calcium
at the borers. If glia are inee releasingtransmitters, methos such as this shoul
allow researchers to examine exactly where
they are releasing them from.
Robitaille aims to fin out whether astro-
cytes can etect very low levels of synap-tic transmission — a neuron passing just
This approach is “like an aTom bomb” going off in The cell 
Nature.com
For more on gliaresearch, visit:
go.nature.com/7u635r
11 NOVEmbER 2010 | VOL 468 | NATURE | 161
© 20 Macmillan Publishers Limited. All rights reserved10

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