387
A neuronglia signalling network in the active brain
Paola Bezzi* and Andrea Volterra
Glial cells are active partners of neurons in processing
information and synaptic integration. They receive coded
signals from synapses and elaborate modulatory responses.
The active properties of glia, including long-range signalling
and regulated transmitter release, are beginning to be
elucidated. Recent insights suggest that the active brain should
no longer be regarded as a circuitry of neuronal contacts, but
as an integrated network of interactive neurons and glia.
Addresses
Department of Pharmacological Sciences, Centre of Excellence for
Neurodegenerative Disorders, University of Milan, Via Balzaretti 9,
20133 Milan, Italy
*e-mail: Paola.Bezzi@unimi.it
e-mail: Andrea.Volterra@unimi.it
Current Opinion in Neurobiology 2001, 11:387394
0959-4388/01/$ see front matter
2001 Elsevier Science Ltd. All rights reserved.
Abbreviations
AMPA -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
GABA -amino butyric acid
NMDA N-methyl D-aspartate
OPC oligodendrocyte precursor cell
PSC postsynaptic current
Introduction
Glia represent the most numerous group of brain cells, and
their roles in providing structural, metabolic and trophic
support to neurons are well established [1]. Over the past
decade, an increasing number of observations have
progressively challenged the classical view that places glial
cells, including astrocytes and oligodendrocytes in the
central nervous system, and Schwann cells in the periph-
eral nervous system, in a subservient position to neurons.
For example, synaptic transmission may propagate to the
neighbouring glia and activate them by elevating levels of
internal calcium [24]. In turn, calcium rises in glial cells
start signalling to neurons [5,6], including the regulated
release of transmitters. This unexpected active property of
glia and the possible existence of rapid regulatory
cross-talks between neurons and glia during synaptic
transmission have stimulated a wave of new studies.
Here we review advances in the past few years that are revo-
lutionising our views on how glial cells participate in synaptic
integration, and, even more importantly, on how the active
brain functions to process information. Major advances have
also been made in understanding the role of neuronglia
signalling interactions in the developing brain, a subject that
has been excellently reviewed recently in this series [7].
The neuronglia network
Using a combination of functional recording and ultrastruc-
tural analysis, recent work has given new dimensions to the
neuronglia dialogue in the active brain. Most notably,
Bergles et al. [8] have reported the existence of direct
chemical synapses between neuronal and glial cells (in this
case, oligodendrocyte precursor cells [OPCs]) in the
hippocampus. They found that, in OPCs, stimulation of
neuronal afferents induced -amino-3-hydroxy-5-methyl-
4-isoxazole propionic acid (AMPA) receptor-dependent
inward currents, whose quantal nature and fast kinetics
correlate well with glutamate released from a presynaptic
terminal directly facing the glial receptors. Electron
microscopy images support the existence of such neuron-
OPC synapses.
Another type of direct contact between neurons and glia,
this time via electrical coupling through gap-junctions, has
been reported in cultured brain cells [9] and in the locus
coeruleus in situ [10]. Although electrotonic coupling was
found to be stronger in the early stages of development,
the in situ study detected its presence in adult tissue as
well, and showed that electrical changes in glia affect
neuronal excitability. Whether electrical connectivity is a
widespread form of neuron-glia communication in the
brain or a peculiarity of the locus coeruleus remains to be
established. For instance, a recent study that analysed the
distribution of gap-junction channels in a number of areas
of the adult rat brain by freeze fracture replica immuno-
gold labelling failed to identify junctional proteins
connecting neurons and glia [11].
As for neurons and glia that are not directly connected,
Ventura and Harris [12] have carried out a detailed three-
dimensional reconstruction of their structural relations in
the hippocampal stratum radiatum. About 50% of the
synapses in this region have astrocyte processes that are
intimately apposed, and in 30% of the synapses an as
trocyte process separates two neighbouring synapses.
Astrocytes almost exclusively surround synapses that are
rich in docked vesicles (i.e. with a high probability of
neurotransmitter release). The heterogeneity of
synapseastrocyte relations in the hippocampus extends
to the functional properties of astrocytes, and subpopula-
tions of these cells with distinct electrophysiological
properties, levels of cell-to-cell coupling and topographical
distribution have been described [13].
An elegant study by Kettenmann and co-workers [14]
focusing on the functional organisation of cerebellar
Bergmann glia reveals even more subtle levels of glial spe-
cialisation. Apparently, these highly ramified cells consist
of hundreds of independent compartments, called glial
microdomains by Kettenmann and co-workers, that are
capable of autonomous interactions with the particular
group of synapses that they ensheath. Thus, stimulating
the adjacent parallel fibers induces localised elevations of
388 Signalling mechanisms
Figure 1
2 acid (GABA), noradrenaline, acetylcholine, dopamine and
5 spill out of the cleft at a concentration sufficient to bind
6 and activate receptors located on the adjacent glial plasma
1
7 classes of glial glutamate receptors.
3 4
Current Opinion in Neurobiology
Repertoire of functional interactions in the neuronglia signalling
network. Neurons are shown in pale yellow, generic glial cells in pink.
Classical forms of rapid communication involve homocellular signalling,
such as chemical synaptic transmission between nerve cells (1) and
electrotonic coupling through gap-junction channels between glial
cells (2). Recent observations indicate, however, that chemical
synapses exist also between a presynaptic neuron and a postsynaptic
glial cell (3; data from [8] ), as well as that gap-junctions could
directly couple a glial cell to a neuron (4; data from [5,9,10]).
Additional forms of heterocellular neuronglia signalling have been
documented. Intense synaptic neurotransmission may lead to the
activation of perisynaptic glial cells. Neurotransmitters spill out of the
cleft at sufficient concentration to bind and stimulate receptors located
on the adjacent glial cell plasma membranes (5; data from
[24,15,16,17,18]). But glial cells can also actively respond to
stimulations, by releasing neuroactive transmitters, and thereby can
modulate the function of adjacent neurons (6; data from
[6,15,32,34,35,40,41,45]). Glial cells can release transmitters
also onto other surrounding glial cells to extend their range of
signalling (7; data from [21,22,23,25,27,29,32]). Overall, it is
highly conceivable that brain activity involves the interactive
concurrence of many, if not all, of the above forms of communication.
On the basis of these insights, we propose that the active brain
functions as an integrated signalling network of both neurons and glia.
intracellular calcium ([Ca2+]i) in the Bergmann glia; these
elevations are restricted to small areas of 100 m2 or less
just about the size of a single microdomain.
These advances demonstrate the existence of a wide range
of rapid communication modes between neurons and glia,
including direct chemical and electrical signalling
(Figure 1). In addition, glial cells reveal new aspects of
their cellular heterogeneity and subcellular organisation,
indicating a previously underestimated level of complex-
ity and functional specialisation.
Synaptic activation of glia
An increasing number of studies report the activation of
perisynaptic glia during neurotransmission. Calcium eleva-
tions in glial cells in response to adjacent neuronal activity
have been observed recently at several different synapses
of both the central and the peripheral nervous system, and
neurotransmitters as diverse as glutamate, -amino butyric
adenosine have been implicated in glial activation
[14,15,16,17,18] (see also Update). The evidence
implies that transmitters released during synaptic activity
membranes. Dzubay and Jahrs [16] study at the climbing
fiber-Purkinje cell synapse provides a quantitative esti-
mate of the concentration of the synaptically released
glutamate outside the cleft. These authors calculated a
value of 160190 M, which is significantly lower than in
the cleft (1 mM), but still high enough to activate all
Not only are glial cells activated during synaptic transmis-
sion, but some of their specific properties, such as
gap-junctional communication, also seem to be dynamical-
ly regulated by the surrounding neuronal activity [19].
Similarly, high-frequency firing in myelinated CA1
hippocampal fibers enhances phosphorylation of the
oligodendrocyte-specific protein myelin basic protein.
Reactive oxygen species and/or nitric oxide are implicated
in this neuron-to-glia signalling pathway [20].
The available data document well the extension of synaptic
signalling to glial domains (Figure 2); however, many unan-
swered questions remain concerning the conditions for glial
activation and its characteristics. For example, do glia
respond to any level of neuronal activity or does a certain
threshold exist? Is their activation graded and correlated
with the level of ongoing neuronal activity? Do glial cells
codify the information received from neurons into the
spatio-temporal characteristics of their calcium elevations?
Gliotransmission
Elevation of internal calcium levels in glial cells represents
the start of further communication; both highly localised
and long-range calcium signalling is observed, each possi-
bly having a distinct function (Figure 2). [Ca2+]i rises that
are confined to single microdomains of Bergmann glia in
response to neuronal stimulation [14], as discussed
above, are a typical example of focal communication.
These rapid and spatially restricted calcium bursts proba-
bly underlie quick responses to the input signal, and help
integrate the messages at a local level. Alternatively,
[Ca2+]i increases may spread in the glial network in the
form of slow, regenerative calcium waves. In cell cultures,
such waves often travel for millimetres, possibly underlying
the spatial transfer of information and coordination of
distant circuits of the neuronglia network.
Thanks to advances in optical monitoring techniques, it has
been recently discovered that additional chemical signals,
notably glutamate and ATP, propagate in astrocytic
networks in the form of regenerative waves that accom-pany
 A neuronglia signalling network in the active brain Bezzi and Volterra 389

Figure 2

Chemical signalling underlying the neuronglia

bidirectional communication. Neurotransmitters Synaptic activation of glia
spilling over from active synapses can Glutamate
stimulate receptors on glial cells, resulting in GABA Neurons
internal calcium elevation and activation of the Noradrenaline
glial cell (synaptic activation of glia; black Acetylcholine
arrow). Several different transmitters have been Adenosine
shown to start neuron-to-glia signalling at Gliotransmission
Dopamine
various synapses of either the central or Ca2+, IP3
peripheral nervous system (data from Glutamate
[15,16,17,18]) (see also Update). [Ca2+]i ATP
rise in the active glial cell (depicted in pale Glia Prostaglandins
yellow; pink indicates inactive cells) can NO
produce a neuromodulatory response by
triggering transmitter release Neuromodulatory glia
(neuromodulatory glia; blue arrows). This glia- Glutamate
to-neuron signalling can act locally, feeding D-serine
back a response to the original stimulatory NO
synaptic domain, or distally, to modulate a Neurons
different synaptic domain, if the activation
signal is spatially propagated in the glial Current Opinion in Neurobiology
network (see below). Various transmitters may
sustain glia-to-neuron signalling, although the network with spatial expansion of the original calcium waves are accompanied by waves of
best collected evidence so far is for calcium- input. Mostly studied in cultured astrocytes, extracellular mediators, such as ATP or
dependent exocytosis of glutamate from gliotransmission has been classically glutamate. Therefore, gliotransmission must
astrocytes (data from monitored as intercellular waves of calcium also proceed through autocrine/paracrine
[6,15,32,34,35,37,4042,45]). A third elevation (pale yellow cells) and thought to glia-to-glia signalling, possibly involving
form of communication, here called depend on intracellular signal (e.g. inositol additional transmitters such as prostaglandins
gliotransmission (red dashed lines and triphosphate [IP3]) diffusion through gap- and nitric oxide (data from
arrows), allows signals to spread in the glial junctions. But recent work indicates that [21,22,23,25,27,29,31,32]).

the calcium waves [21,22,23]. These important observa-
tions indicate that the two mediators are impli-cated in
gliotransmission. Indeed, a role for ATP in the mechanism
of propagation of calcium waves has now been identified.
Until a few years ago, calcium signals were thought to
spread between connected astrocytes only by the diffusion
of internal mediators, such as inositol triphosphate, through
open gap-junction channels. Propagation in astrocyte
cultures has now been observed even through areas that are
cell-free, implying the existence of an extracellular
signalling pathway [24]. Kater and co-workers [25] have
elegantly shown that ATP is released from one astrocyte to
act at ATP receptors on the neighbouring ones. ATP-
dependent calcium signalling is mediated by metabotropic
purinergic P2Y receptors coupled to calcium release from
internal stores [26]. In cell cultures, this process appears to
be highly interactive with the gap-junction pathway,
because gap-junction perturbations markedly affect wave
propagation and ATP signalling [2730]. Because ectopic
expression of connexins, the protein constituents of the two
hemichannels forming a gap-junction, boosts ATP release,
Nedergaard and co-workers [28,29] have proposed that
ATP is released from gap-junction hemichannels.
Further observations suggest that calcium waves are a
complex and heterogeneous phenomenon. For example,
Newman [23] has shown in the intact retina that waves
appear to propagate between the resident glial cells
(astrocytes and Mller glia) by two distinct mechanisms,
one involving gap-junctional communication, the other
ATP-dependent signalling. In cell cultures, a new propa-
gation pathway that depends on nitric oxide/G kinase but
is independent of ATP has been described recently [31].
Prostaglandins (PGs) too are likely to be major players.
We and our co-workers [32] have found that
prostaglandins may have a critical role in the calcium-
dependent mechanism leading to regenerative glutamate
release [32]. Apparently, PGE2 is rapidly released from
astrocytes when glutamate activates its receptors, to
enhance and extend the calcium signalling started by this
neurotransmitter. Interestingly, similar PGE2-dependent
events are stimulated by activation of P2Y purinoceptors
[33]. These data suggest that glial cells might use ampli-
fying autocrine or paracrine loops, sustained by local
chemical signalling through PGE2 and other mediators,
so to allow signals to reach more distal domains.
Overall, we have just begun to appreciate that glia receive,
elaborate and transfer information. In this light, our
present understanding of gliotransmission is probably quite
primitive. Many recent advances rely on studies
performed in cell culture where the glial network organisa-
tion may not exactly mirror the one in the intact brain.
Moreover, different studies activate glial cell communication
through different stimuli (mechanical, electrical and chemi-
cal stimuli), which might trigger different signalling
mechanisms. To consolidate and advance the present knowl-
edge, more standardised experimental conditions and more
refined models should be used in future studies, including
intact tissue preparations, for which initial findings have
390 Signalling mechanisms
already confirmed that glial signal propagation may take
place in the form of calcium waves [23,34] and If glia can release neurotransmitters in a regulated manner,
autocrine/paracrine amplifications [32].
Glial exocytosis?
The spatiotemporal characteristics of glial [Ca2+]i eleva-
tions might not only encode information received from
neurons [4], but also represent the basis for regulation of
feedback responses to them. Indeed, [Ca2+]i rises in glial
cells are known to trigger transmitter (glutamate) release
that modulates neuronal function [6,32].
Two recent studies try to correlate the extent and dynam-
ics of calcium elevation with glutamate release [35,36].
Parpura and Haydon [35] have used photolysis of a calci-
um cage to induce quantitatively controlled [Ca2+]i rises in
astrocytes. They found that modest [Ca2+]i elevations (in
the range of 80140 nM) are sufficient to trigger glutamate
release. In addition, in some cells further calcium rises
induce more glutamate release, suggesting that there is a
doseresponse relation between the two events. Pasti et al.
[36] elicited specific patterns of oscillatory [Ca2+]i
responses in astrocytes via transmitter stimulations, and
observed the corresponding patterns of glutamate-depen-
dent responses in appropriate sniffer cells (HEK cells
transfected with N-methyl D-aspartate [NMDA] recep-
tors). The synchronicity between the two types of event
suggests that astrocyte oscillations induce repetitive
episodes of glutamate release. In particular, any [Ca2+]i
oscillation with a peak greater than 550 nM would induce
an episode of glutamate release.
These findings are consistent with a highly regulated and
physiologically relevant mechanism of release. Indeed, the
observed properties of the Ca2+-dependent mechanism
strongly suggest that it occurs by a process resembling
neuronal exocytosis. First of all, the release is sensitive to
blockers of neuronal exocytosis, including tetanus neuro-
toxin, botulinum B toxin and bafilomycin A1 [32,36,37],
which in contrast have no effect on other forms of astrocyte
glutamate release, such as transporter-mediated release or
swelling-induced release ([32]; and P Bezzi et al., unpub-
lished data). In support of exocytosis is also the observation
that Ca2+-dependent glutamate release onto sniffer cells
evokes NMDA receptor-dependent currents with fast
kinetics resembling quantal release events [36]. Finally,
several of the proteins forming the exocytotic machinery in
neurons have now been identified in astrocytes; moreover,
some of them, like synaptobrevin, have been localised at
the membrane of vesicular organelles [38,39].
A conclusive demonstration of glial exocytosis will
require that the glutamate-containing vesicles are identi-
fied ultrastructurally and that the dynamics of their fusions
with the plasma membrane are shown directly. Given that
glial cells have physiological properties that are distinct
from neurons, glial exocytosis might turn out to have
important differences from its neuronal counterpart.
Neuromodulatory glia
this process must be a fundamental component of its
dialogue with neurons during synaptic activity (Figure 2).
Recent in vitro work by Haydons [40,41] laboratory
provides the first indication that astrocyte activation has
important consequences on synaptic function. The group
found that, independent of the nature of the synapse
(excitatory or inhibitory), stimulation of an astrocyte while
evoking synaptic activity produced a reduction in the
postsynaptic current (PSC) response. In contrast, astrocyte
stimulation enhanced the frequency (not the amplitude) of
miniature PSCs elicited by spontaneous quantal release
events. Haydon and co-workers explained the two distinct
modulatory effects by the interaction of astrocyte-released
glutamate with neuronal receptors of distinct type and
localisation in the two cases: presynaptic metabotropic
glutamate receptors for reduction of evoked PSCs;
extrasynaptic NMDA receptors for enhancement of
miniature PSC frequency.
Glial cells might modulate neuronal NMDA receptor func-
tion not only through released glutamate, but also through
D-serine, a physiological ligand at the glycine site of the
NMDA receptor [42]. Immunoreactivity for D-serine and its
synthetic enzyme, serine racemase, is found in the brain to be
confined to glial cell populations [43], from which the amino
acid can be released on activation of AMPA/kainate receptors.
To support and extend the in vitro findings, a few elegant
studies in situ provide direct demonstrations of the active
modulatory role played by glial cells in synaptic transmis-
sion. Two complementary studies by the group of
Carmignoto and our group [4,32], in collaboration, have
revealed the existence of a rapid bidirectional communica-
tion system between hippocampal CA1 pyramidal neurons
and their neighbouring astrocytes on the basis of the
reciprocal exchange of glutamatergic signals.
A second group of studies by Robotaille and co-workers
[18,44,45] has revealed the modulatory role of perisynap-
tic Schwann cells at the neuromuscular junction. Under
high-frequency stimulation, motor neuron terminals were
shown to send a chemical signal (probably through
released acetylcholine and adenosine) to the associated
Schwann cell, which activates internal G-protein-depen-
dent calcium signalling, resulting in a feedback inhibitory
response on neurotransmission, possibly mediated by glial
release of nitric oxide.
A similar modulatory glial loop underlies activity-depen-
dent potentiation of inhibitory synaptic transmission in the
hippocampus [15]. Kang et al. [15] found that repeated
firing of GABAergic interneurons synaptically connected
to CA1 pyramidal cells recruits GABAB receptors of near-
by astrocytes with ensuing [Ca2+]i elevation in these cells,
which in turn potentiates inhibitory transmission, possibly
through released glutamate.
 A neuronglia signalling network in the active brain Bezzi and Volterra 391

Figure 3

Working hypothesis on the impact of (a) (b)

inflammation on neuronglia signalling and its
neuropathological consequences. (a) In
normal conditions, synaptic activity may start
bidirectional signalling between neurons and
astrocytes serving a physiological modulatory
function (arrows indicate the communication
modes defined in Figure 2). Microglial cells,
the brain resident macrophages responsible
for local immunosurveillance, are quiescent
and have sparse distribution. (b) When a local
inflammatory reaction is triggered in the brain
(as it may occur, for example, in Alzheimers
disease or in the AIDS neuropathology),
microglial cells converge to the site of injury,
become activated and start releasing a
number of mediators, notably inflammatory
cytokines such as interleukins (IL)-1 and IL-6
and tumour-necrosis factor- (TNF-), that
alter profoundly the properties of astrocytes.
Consequently, the neuronglial signalling
might be perturbed. For instance, astrocytes
exposed to IL-1 respond to stimulations with
Neurons
Resting
Astrocytes
microglia
Neurons
an expanded range of propagation of calcium
waves, that now involves a higher number of
cells (in pale yellow, with respect to pink
inactive cells) (data from [48]). If more
astrocytes undergo [Ca2+]i elevation, more
sites of transmitter release and glia-to-neuron
signalling are likely to be activated than in
normal conditions. Indeed, we report that
Inflammatory
cytokines
Activated
microglia
Current Opinion in Neurobiology
Ca2+-dependent glutamate release from
astrocytes is strongly potentiated in the
presence of activated microglia, which
apparently acts through TNF-. Deranged
glia-to-neuron glutamate signalling eventually
leads to reduced viability of the surrounding
neurons (P Bezzi, M Domercq et al.,
unpublished data).

Finally, Newman and Zahs [34] found that activation of
retinal glial cells (astrocytes and Mller cells) in the rat
eyecup preparation modulates neuronal firing activity
evoked by light in the ganglion cell layer, causing inhibi-
tion in most cases, excitation in a few cases. Inhibition is
likely to be mediated by inhibitory interneurons stimulated
by glutamate released from the glial cells.
junctional proteins are observed [48,49]. Moreover, calcium
wave transmission is potentiated after upregulating P2-recep-
tor-mediated, ATP-dependent signalling. In turn, P2 receptor
activation enhances cytokine signalling, with the possible
start of an amplifying cycle [50]. Through this mechanism,
inflammation may cause a perturbed transmission of data
from glial networks to neuronal circuits (Figure 3).

Collectively, the experimental work of the past few years
provides a strong experimental basis for asserting that
glial cells are integral and active components of the func-
tional brain network. However, the specific roles that glia
have in different types of activity and circuits remain to
be established.
Network alterations in pathology
Appreciation that brain activity involves interactive sig-
nalling between neurons and glia opens new perspectives
for understanding the pathogenesis of brain diseases. Thus,
glial alterations in pathology might turn out to have a more
profound impact on the functionality of the associated neu-
ronal circuits than previously thought and, in some cases,
even to be the primary cause of the neuropathology (for a
recent demonstration, see [46]). In this light, brain inflam-
mation is known to cause major changes in glial cells,
particularly in astrocytes and microglia; however, the
impact that such changes have on the functional relations of
glial cells between themselves and with neurons has not
been explored. Recent work addresses this issue.
Not only inflammation is found to produce profound alter-
ations in the intimate structural relations between neurons
and astrocytes [47], but also the glial network properties are
modified in the presence of inflammatory cytokines such as
interleukin-1. Coordinated changes in the expression of
Work in our own laboratory reinforces this idea. We have
found that Ca2+-dependent glutamate signalling between
astrocytes and neurons is potently amplified in the
presence of inflammatory microglia, leading to excitotoxic
neuronal damage. Again, an inflammatory cytokine,
tumour-necrosis factor-, is implicated in the pathological
switch (P Bezzi, M Domercq et al., unpublished data).
Altered glial network properties may have an important
pathological role in cerebral ischemia, and may contribute
to the secondary amplification of cell injury. Apparently,
astrocyte gap-junction channels remain open during
ischemia [51], providing a linking pathway between dying
astrocytes in the core of an evolving infarct and the sur-
rounding, potentially viable, cells. Indeed, an elegant study
by Lin et al. [52] shows that pro-apoptotic death signals
can spread trans-cellularly through the open gap-junctions.
Neuronglia coupling and imaging of the
active brain
Normal brain function relies on the balance between ener-
gy-requiring activity and metabolic supply. Recent data
indicate that the two processes are tightly coupled and the
cycling of the neurotransmitter glutamate through astro-
cytes is a pivotal element in this coupling. Most glycolytic
glucose consumption in the brain occurs in astrocytes,
which subsequently export lactate to neurons as a substrate
392 Signalling mechanisms
for oxidative metabolism (for recent data, see [53,54]). By
contrast, glutamate released from synapses is primarily
taken up into the astrocytes, where it is converted to gluta-
mine and, as such, returned to neurons. On the basis of
these observations, Pellerin and Magistretti [55] proposed a
model in which astrocytic glucose consumption is directly
coupled to uptake of synaptic glutamate into astrocytes.
Such a model implies that glia-to-neuron energy supply is a
function of the level of ongoing synaptic activity. 13C NMR
spectroscopy studies in the cortex of living rats and humans
has confirmed the validity of this model [56]. Moreover, a
1:1 stoichiometry has been determined between astrocytic
glucose consumption and glutamate uptake, which
indicates that astrocyte glycolysis is almost exclusively
driven by glutamate cycling [56,57].
The above conclusions have major implications for brain
imaging studies. Recent techniques such as positron-emis-
sion tomography and functional magnetic resonance
imaging allow to see the brain at work and to identify the
areas activated by specific tasks. These techniques do not
detect brain activity directly, but rather measure signals
that reflect brain energy consumption. The revealed stoi-
chiometric coupling between synaptic activity and glucose
consumption indicates, however, that signals monitored in
functional imaging indirectly contain quantitative informa-
tion on neuronal activity. More precisely, they quantitate
brain excitation that is, the overall activity of excitatory
synapses, given that brain inhibition is significantly less
energy demanding [58].
Therefore, neuronglia coupling provides the functional
basis for incorporating biological information into psychol-
ogy-designed studies. On this basis, as recently proposed
by Magistretti et al. [59], we can now start the exciting
project of bridging psychological understanding of behav-
iour and cognition with neurobiological understanding of
brain function.
Conclusions
The wave of new findings here reviewed demonstrates
that glial cells, and not only neurons, are actively involved
in processing information and synaptic integration. These
insights stimulate a new view, according to which the
active brain should no longer be regarded as a network of
neuronal contacts only, but instead as an integrated circuit
of interactive neurons and glia.
Our understanding of this intense neuronglia cross-talk is
only just beginning, and the next few years should clarify
a number of important aspects, such as the full repertoire
of morpho-functional relations existing between the two
types of cells; the exact codes they use to exchange infor-
mation; the specific conditions under which glial cells are
recruited into neurotransmission and the contribution they
give to the integrative properties of the brain or to its
derangement in pathology. To this end, one foresees the
need of major investment in the set-up of experimental
models and technology approaches that allow the integrat-
ed recording of neuronal and glial activities, as well as the
dissection of their causal interrelations.
Update
Extending their previous observations [60], Barres and
co-workers [61] have recently documented another sur-
prising function of glia in its integration with the neuronal
circuitry: the control of the number of synaptic contacts
that neuronal cells make with each other. The authors
show that the astrocyte signals (yet to be identified) not
only increase the number of mature functional synapses on
central nervous system neurons in vitro, but also are neces-
sary for maintaining an efficient synaptic connectivity.
These findings raise the possibility that glial cells play an
active role in synaptic plasticity phenomena.
Two recent studies [62,63] provide evidence supporting
the existence of additional pathways leading to activation
of astrocyte signalling and neuronglia integration by
synaptic transmitters. Such pathways would be sustained
by dopamine in the pre-frontal cortex and acetylcholine in
the hippocampus, acting through astrocyte dopamine D2
and cholinergic nicotinic receptors, respectively.
Acknowledgements
Our work is supported by grants from the European Community
(QLK6-CT-1999-02203), Ministero dellUniversita e Ricerca Scientifica e
Tecnologica of Italy (MURST, Co-finanziamento 2000-01), and Istituto
Superiore di Sanit of Italy (II Progetto Nazionale AIDS, 2/246).
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