Download Communication between neurons and astrocytes: relevance to the

JOURNAL OF NEUROCHEMISTRY
| 2009 | 108 | 533–544
doi: 10.1111/j.1471-4159.2008.05830.x
Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy
Abstract
Neuromodulation is a fundamental process in the brain that
regulates synaptic transmission, neuronal network activity and
behavior. Emerging evidence demonstrates that astrocytes, a
major population of glial cells in the brain, play previously
unrecognized functions in neuronal modulation. Astrocytes
can detect the level of neuronal activity and release chemical
transmitters to influence neuronal function. For example, recent findings show that astrocytes play crucial roles in the
control of Hebbian plasticity, the regulation of neuronal excitability and the induction of homeostatic plasticity. This review
discusses the importance of astrocyte-to-neuron signaling in
different aspects of neuronal function from the activity of single synapses to that of neuronal networks.
Keywords: astrocytes, Ca2+ signaling, glia, gliotransmission,
synaptic plasticity, synaptic transmission.
J. Neurochem. (2009) 108, 533–544.
We now understand that the traditional view of astrocytes as
merely supportive cells providing only structural and metabolic support to neurons is limited and studies of the last
20 years show that astrocytes exert a series of complex
functions that go well beyond the uptake and recycle of
neurotransmitters and the buffering of extracellular potassium (Volterra and Steinhauser 2004; Allen and Barres 2005;
Volterra and Meldolesi 2005; Fellin et al. 2006b; Haydon
and Carmignoto 2006; Iadecola and Nedergaard 2007).
Morphologically, astrocytes are characterized by a highly
ramified structure of thin processes with which they contact
neurons, blood vessels and other astrocytes. Astrocyte–
astrocyte contacts mediate gap junction coupling between
adjacent glial cells to form a cellular network called the
astrocytic ‘syncytium’ (Giaume and McCarthy 1996).
Although astrocytes form a highly interconnected network,
they structurally occupy separate domains with very limited
or no overlap between the region occupied by one astrocyte
and the regions occupied by its neighboring cells (Bushong
et al. 2002; Halassa et al. 2007b) (Fig. 1b). Within the
volume of one astrocytic domain, it has been estimated that a
single glial cell can contact up to 105 synapses (Bushong
et al. 2002; Halassa et al. 2007b) and hundreds of dendrites
(Halassa et al. 2007b) (Fig. 1a). The contact between the
astrocyte and the neuron is a highly dynamic structure
(Hirrlinger et al. 2004; Haber et al. 2006) and the extent of
astrocytic coverage of the neuronal terminals is activitydependent (Genoud et al. 2006). This complex anatomical
organization serves a number of different functional roles.
For example, astrocytes display a form of excitability that is
based on changes in the intracellular Ca2+ concentration
(Cornell-Bell et al. 1990) and are capable of releasing a
number of signaling molecules that have a complex effect on
neuronal function (Haydon 2001; Newman 2003; Fellin and
Carmignoto 2004). Although it has been shown that the
release of chemicals from astrocytes influences a variety of
brain processes such as the genesis (Christopherson et al.
2005) and stabilization of synapses (Ullian et al. 2001), the
Received September 16, 2008; revised manuscript received October 28,
2008; accepted November 20, 2008.
Address correspondence and reprint requests to Tommaso Fellin,
Department of Neuroscience and Brain Technologies, Italian Institute of
Technology, Via Morego 30, 16163 Genova, Italy.
E-mail: [email protected]
Abbreviations used: IP3, inositol 1,4,5-trisphosphate; LTD, long-term
depression; LTP, long-term potentiation; LY367385, (S)-(+)-a-Amino-4carboxy-2-methylbenzeneacetic acid; mEPSC, miniature excitatory
postsynaptic current; mGluR, metabotropic glutamate receptor; OD,
ocular dominance; t-ACPD, 1-aminocyclopentane-trans-1,3-dicarboxylic
acid; TNFa, tumor necrosis factor a; TTX, tetrodotoxin.
Ó 2008 The Author
Journal Compilation Ó 2008 International Society for Neurochemistry, J. Neurochem. (2009) 108, 533–544
533
534 | T. Fellin
(a)
(b)
Fig. 1 Structural organization of astrocyte-neuron networks. (a)
Confocal image showing GFP-expressing astrocytes (green) and a
biocytin-filled neuron (red). A single astrocyte contacts multiple
dendrites of a single neuron and single neurons are associated with
multiple astrocytes. Reproduced with permission from (Halassa et al.
2007b), copyright 2007 from The Journal of Neuroscience. (b) The
astrocytic network is structurally organized in non-overlapping domains.
Each astrocyte occupies a distinct volume (domain) with very little or no
overlap with the volumes (domains) occupied by other astrocytes.
control of the vasculature tone (Zonta et al. 2003; Mulligan
and MacVicar 2004; Metea and Newman 2006; Takano et al.
2006) and the modulation of neuronal excitability, many
aspects of this astrocyte-to-neuron signaling are still incompletely understood (Agulhon et al. 2008). This review first
highlights some recent results describing the properties of
Ca2+ signaling in astrocytes in vivo and then discusses some
examples of signaling between astrocytes and neurons
focusing on the importance of astrocyte-to-neuron communication in the modulation of neuronal function at the level of
single synapses and neuronal networks.
critical period usually results in little plasticity, Muller and
Best show that transplantation of immature astrocytes from
newborn kittens into the visual cortex of adults cats is able to
induce OD plasticity after the end of the critical period
(Muller and Best 1989). Based on these results, the authors
hypothesized that immature astrocytes release a permissive
factor that allows OD plasticity to occur and suggested that
the end of the critical period could coincide with the
maturation of cortical astrocytes.
Although the molecule secreted by astrocytes that restores
OD plasticity was not identified, this study suggested that
astrocytes are capable of releasing neuroactive molecules and
thus have the potential to be not only supportive but also
signaling cells in the brain. Since then, a number of different
investigations, performed mainly in vitro and in situ, have
identified several molecules released by astrocytes in a
process named ‘gliotransmission’, including, among others,
glutamate (Parpura et al. 1994; Bezzi et al. 1998), ATP
(Cotrina et al. 1998; Coco et al. 2003), D-serine (Mothet
et al. 2000) and tumor necrosis factor a (TNFa) (Stellwagen
and Malenka 2006). The study of the intracellular signaling
pathways regulating the release of ‘gliotransmitters’ has
revealed a central role of cytosolic Ca2+ concentration for
some of these molecules. The use of fluorescent Ca2+
indicators demonstrated that astrocytes display spontaneous
and neuronal activity-evoked oscillations in their intracellular
Ca2+ concentration (Cornell-Bell et al. 1990; Charles et al.
1991) which can then trigger the release of gliotransmitters
such as glutamate (Parpura et al. 1994), D-serine (Mothet
et al. 2005) and ATP (Coco et al. 2003). These findings led
to the proposal that astrocytes are excitable cells, yet their
excitability is not based on changes in the voltage of their
membrane but rather on changes in the intracellular concentration of the Ca2+ ion (Halassa et al. 2007a).
Astrocytes: from supportive to signaling cells
For several decades, the inability of astrocytes to fire action
potentials has supported the view of these glia as supportive,
non-excitable cells. Some of the first evidence that astrocytes
are signaling cells that can release chemical messengers to
affect neuronal function was provided almost 20 years ago
(Muller and Best 1989). In that study, the authors showed
that injection of immature astrocytes into the visual cortex of
adult cats in vivo reopens the window of ocular dominance
(OD) plasticity. Since its discovery more than 40 years ago
(Wiesel and Hubel 1963), OD plasticity has been a preferred
model to investigate the cellular and molecular mechanism of
plasticity in vivo. In higher mammals, the visual cortex is
organized in OD columns consisting of neurons responding
preferentially to one but not the other eye. If during a precise
postnatal time period, called the critical period, one eye is
deprived of vision, there is a dramatic change in the neuronal
circuits underlying the OD columns because of the imbalance
of visual inputs. OD columns responding to the deprived eye
shrink while the OD columns responding to the non-deprived
eye expand. Although visual deprivation performed after the
Ó 2008 The Author
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Glial regulation of neuronal activity | 535
Ca2+ signaling in astrocytes: lesson from in vivo
experiments
The introduction of two-photon microscopy has revolutionized fluorescence imaging permitting in vivo functional
imaging with cellular resolution (Denk et al. 1990; Helmchen and Denk 2005) and allowing an appreciation of the
complexity of the Ca2+ signaling dynamics of astrocytes in
vivo. Using this technique, Hirase et al. first described the
occurrence of Ca2+ signals in cortical astrocyte from living
rats (Hirase et al. 2004). In anesthetized animals, more than
60% of the imaged astrocytes displayed a complex pattern of
changes in the intracellular Ca2+ concentration, including
brief (5–50 s) repetitive spikes and long-lasting (>50 s)
plateaus. Plateaus and Ca2+ spikes occurred with a relatively
low frequency (0.1 event/min) under basal conditions and
showed a limited degree of correlation among nearby
astrocytes (Hirase et al. 2004; Nimmerjahn et al. 2004).
Under basal conditions and in the absence of sensory
stimulation, Ca2+ signaling in astrocytes is thus organized in
domains that largely coincide with the tiling organization of
the structural domains (Fig. 2a and b).
In addition to spontaneous oscillations, in situ studies
have demonstrated that neuronal activity can trigger Ca2+
elevations in astrocytes (Porter and McCarthy 1996; Pasti
et al. 1997). The first evidence suggesting that this could
happen in vivo was the observation that the application of the
GABAA receptor antagonist bicuculline (Hirase et al. 2004)
or picrotoxin (Gobel et al. 2007), which increases neuronal
activity by triggering epileptic-like discharges, resulted in an
(a)
(b)
(c)
(d)
Fig. 2 Astrocytic Ca2+ signaling in vivo is organized in functional domains. (a) Spontaneous Ca2+ oscillations are shown for two different
time points t1 (left) and t2 (right). Spontaneous Ca2+ signaling in astrocytes occurs independently from the activity of nearby cells and
very limited or no correlation between the activity of different astrocytes is observed (Hirase et al. 2004). (b) The single-cell responsive
map shows that during spontaneous oscillations the functional domains of astrocytic Ca2+ response at t1 and t2 (yellow and blue lines
respectively) largely overlap with the anatomical domains (black lines)
of the astrocytic network. (c) In response to different visual stimuli
(stimulus 1, left; stimulus 2, right) distinct groups of astrocytes respond
with Ca2+ oscillations (Schummers et al. 2008). Visual stimuli with, for
example, different orientations elicit Ca2+ signaling in specific groups
of astrocytes with some cells responding preferentially to one orientation and not to others. Groups of 2 to more than 10 astrocytes can
respond to the same visual stimulus (Schummers et al. 2008). (d) The
single-cell responsive map shows that, during activity-evoked signals,
the astrocytic Ca2+ response is organized in functional domains (red
and green lines for stim.1 and stim. 2 respectively) that are larger than
the structural domains (black lines).
Ó 2008 The Author
Journal Compilation Ó 2008 International Society for Neurochemistry, J. Neurochem. (2009) 108, 533–544
536 | T. Fellin
increase in Ca2+ signaling in astrocytes. Additionally, these
Ca2+ signals were correlated between pairs of nearby
astrocytes (Hirase et al. 2004), suggesting that neuronal
activity-driven oscillations may not be limited to single
astrocytes but may occur synchronously in multiple cells.
Subsequently, sensory stimulation was shown to increase
Ca2+ signaling in astrocytes in anesthetized animals. In the
mouse, whisker (Wang et al. 2006), limb (Winship et al.
2007) and odor stimulation (Petzold et al. 2008) causes Ca2+
transients in astrocytes in the barrel, the primary somatosensory cortex and the olfactory bulb respectively, while a
recent study in ferrets (Schummers et al. 2008) demonstrates
that visual stimulation triggers a large increase in astrocytic
Ca2+ in the visual cortex. Typically activity-mediated Ca2+
signals in astrocytes are delayed by a few seconds in relation
to neuronal responses (Wang et al. 2006; Schummers et al.
2008), although a subpopulation of glial cells (Winship et al.
2007) can respond as quickly as neurons. When whisker
stimulation is used to evoke Ca2+ signals in cortical
astrocytes, astrocytic Ca2+ responses peak at a whisker
stimulation frequency that induces the maximal neuronal
response (Wang et al. 2006), suggesting that the astrocytic
response linearly correlates with the strength of the sensory
stimulation. Astrocyte activation by sensory stimulation is
extremely tuned and stimulus selective and display all the
features typical of the neuronal response (Schummers et al.
2008): (i) astrocytes respond to visual stimuli over a
comparable region of nearby neurons and the x–y
two-dimensional receptive field and maximal response of
astrocytes are similar to the neuronal ones; (ii) the Ca2+
response of astrocytes is a function of the orientation and
spatial frequency of the visual stimulus and when compared
to neuronal responses, astrocytes display sharper orientation
and spatial frequency tuning; (iii) single cell-based
orientation preference maps across the cortical surface show
that small groups of cells (from 2 to >10) respond
preferentially to one stimulus orientation and not to others
demonstrating that Ca2+ signaling in astrocytes evoked by
sensory stimulation is organized in functional domains that
are not restricted to single cells but involve multiple
astrocytes (Fig. 2c and d). Whether the astrocytes that form
a functional domain are coupled with each other to form
distinct syncytia or whether they are separately, but
simultaneously activated by neuronal activity is still not
known.
All the in vivo data discussed so far were obtained in
anesthetized animals but confirmation that activity-dependent
Ca2+ oscillations in astrocytes occur in behaving mice comes
from a recent report (Dombeck et al. 2007). When head
restrained mice were free to run on a spherical treadmill and
simultaneous two-photon Ca2+ imaging was performed in the
cortex, Dombeck et al. could observe behaviorally correlated
Ca2+ signals in astrocytes. Large, repetitive Ca2+ signals in
astrocytes are associated with the running behavior and are
temporally correlated in multiple glial cells over a distance of
almost 100 lm (Dombeck et al. 2007).
Taken together these results show that in different preparations from mice (Wang et al. 2006), to rats (Hirase et al.
2004) and ferrets (Schummers et al. 2008), in anesthetized as
well as in behaving animals, astrocytes display a complex
pattern of spontaneous and neuronal activity-driven Ca2+
signals. Spontaneous Ca2+ signals are mostly restricted to
single astrocytes and occur independently of the activity of
neighboring astrocytes (Hirase et al. 2004), while activitymediated Ca2+ oscillations occur in groups of different
astrocytes that respond to the same sensory stimulus (Schummers et al. 2008). Astrocytic Ca2+ signaling is thus organized
in functional domains that, in the case of spontaneous
oscillations, correspond to the non-overlapping anatomical
domain (Fig. 2a and b). In contrast, in the case of activityevoked signals, the functional domains of the Ca2+ response
are larger than the structural domains and can involve several
glial cells (Fig. 2c and d).
Different mechanisms underline the generation of
spontaneous and activity-evoked Ca2+ signals in astrocytes
Astrocytes express a wide range of receptors for different
neurotransmitters (Haydon 2001). In brain slice preparations,
several lines of evidence demonstrate that the astrocytic Ca2+
response to excitatory neuronal activity is largely mediated
by the activation of metabotropic glutamate receptors
(mGluRs) (Pasti et al. 1997). In vivo, application of the
mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) or
t-ACPD evokes robust Ca2+ transients in cortical astrocytes,
while co-application of the mGluR1 antagonist LY367385
and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduces the whisker-evoked Ca2+ response in
astrocytes by more than 70% (Wang et al. 2006). 2-Methyl6-(phenylethynyl)pyridine (MPEP) and LY 367385 alone are
equally effective in inhibiting the whisker-evoked response
(40–50% inhibition), suggesting that both mGluR1 and
mGluR5 contribute to astrocyte activation (Wang et al.
2006). Iontophoretic application of the alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate
receptor antagonist 6-Cyano-7-nitroquinoxaline-2,3-dione
(CNQX) reduces the post-synaptic response with no effect
on whisker-evoked Ca2+ oscillations in astrocytes. These
results suggest that, in vivo, astrocytes can sense glutamate
release at excitatory synapses which in turn activates
metabotropic glutamate receptors on their plasma membrane
to generate intracellular Ca2+ increases. Nonetheless, a
recent study suggests a role for glutamate transporters in the
regulation of astrocytic Ca2+ signaling (Schummers et al.
2008). Application of the glutamate transporter inhibitor
threo-b-Benzyloxyaspartic acid (TBOA) in vivo drastically
reduces Ca2+ signals in astrocytes evoked by visual
stimulation, with a modest increase in the neuronal
responses.
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Glial regulation of neuronal activity | 537
The activity-driven response in astrocytes is extremely
sensitive to the level of neuronal activity: 1% increase in the
isofluorane concentration causes a modest (16%) decrease in
the neuronal response to visual stimulation but a dramatic
(77%) decrease in the astrocytic response (Schummers et al.
2008). This finding suggests that there is a steep threshold for
astrocyte activation and this has been proposed to account for
the sharper tuning to orientation and spatial frequency of the
astrocytic response compared to the neuronal one (Schummers et al. 2008).
Differently from sensory-evoked Ca2+ signals, spontaneous Ca2+ oscillations seem to be generated independently
from neuronal activity (Takata and Hirase 2008). In vivo
application of tetrodotoxin (TTX) to block neuronal action
potential-dependent release at pre-synaptic terminals significantly reduces neuronal activity with no effect on spontaneous Ca2+ oscillations in astrocytes. At the same time,
application of mGluR and purinergic receptor antagonists
does not result in a reduction of spontaneous Ca2+ signals in
astrocyte (Takata and Hirase 2008). These findings agree
with previous studies in brain slice preparations (Nett et al.
2002), suggesting that spontaneous Ca2+ oscillations in
astrocytes do not depend on the activation of glutamate and
purinergic receptors, occur independently of neuronal activity and are probably generated by intrinsic mechanisms.
Altogether these in vivo data demonstrate that Ca2+
signaling in astrocytes is a complex and sophisticated
phenomenon. It consists of a complicated pattern of spikes
and plateaus and has two principal modes of operation: under
basal conditions, when no sensory stimulation is present,
sporadic Ca2+ signals occur mainly in single astrocytes and
independently of neuronal activity (Hirase et al. 2004;
Takata and Hirase 2008). In contrast, in response to sensory
stimulations, astrocytes display increased Ca2+ signaling that
involves multiple glial cells (Schummers et al. 2008) and is
generated by glutamate released at the synapse that activates
receptors (Wang et al. 2006) and transporters (Schummers
et al. 2008) on the astrocytic membrane (Fig. 3a). While
recent evidence shows that these astrocytic Ca2+ signals are
important for the modulation of the arteriole diameter
(Takano et al. 2006) and the regulation of the hemodynamic
response that generates the intrinsic optical signal (Schummers et al. 2008), the following paragraphs will focus on the
importance of Ca2+ signaling in astrocytes in the control of
neuronal excitability and plasticity at the level of single
synapses and neuronal networks.
Fig. 3 Molecular mechanisms underlying the bidirectional communication between neurons and astrocytes. (a) In vivo evidence (Wang
et al. 2006; Schummers et al. 2008) demonstrates that glutamate
released at excitatory synapses binds to mGluR receptors and
glutamate transporters expressed in the astrocytic membrane to
control astrocytic Ca2+ signaling. (b) Astrocytes release glutamate
which modulates plasticity at single hippocampal synapses (Perea and
Araque 2007) and regulates neuronal excitability by activating
postsynaptic receptors (Parri et al. 2001; Angulo et al. 2004; Fellin
et al. 2004; Kang et al. 2005; Perea and Araque 2005; Nestor et al.
2007; Shigetomi et al. 2008). Moreover, astrocytes sense
global changes in network activity and mediate homeostatic plasticity by releasing TNFa to scale synapses (Stellwagen and Malenka
2006).
Gliotransmission: the release of chemical
transmitters from astrocytes
Since the observation that transplantation of immature
astrocytes in the visual cortex of adult cats reopens the
critical period for OD plasticity (Muller and Best 1989),
several studies have shown that astrocytes can release a
variety of different molecules that can have complex effects
on neuronal function (Parpura et al. 1994; Araque et al.
1998; Kang et al. 1998). These studies led to the introduction
of the concept of gliotransmission and of the so-called
‘tripartite synapse’ (Araque et al. 1999) in which astrocytes
are considered together with the pre- and post-synaptic
terminals a third, signaling element at the synapse. For
example, astrocytes release glutamate which acts at the pre(Fiacco and McCarthy 2004; Jourdain et al. 2007; Perea and
Araque 2007) and post-synaptic level (Parri et al. 2001;
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538 | T. Fellin
Angulo et al. 2004; Fellin et al. 2004; Perea and Araque
2005) to modulate synaptic transmission and neuronal
excitability at both excitatory (Bezzi et al. 1998; Pasti et al.
2001) and inhibitory (Kang et al. 1998; Liu et al. 2004)
synapses, while ATP released from astrocytes modulates
neuronal excitability through the activation of purinergic
ionotropic receptors (Gordon et al. 2005). At the same time,
after degradation to adenosine, ATP released from astrocytes
is responsible for activity-dependent heterosynaptic depression at excitatory synapses (Pascual et al. 2005; Serrano
et al. 2006).
It is important to note that a link between gliotransmission
and Ca2+ signaling in astrocytes has been described only for
some of the molecules released by these glia. While Ca2+dependent release has been proven for glutamate (Parpura
et al. 1994; Bezzi et al. 1998), ATP (Coco et al. 2003) and
D-serine (Mothet et al. 2005), for many other molecules the
Ca2+-dependency has not been proven or not tested yet.
Furthermore, different routes of release for the same
gliotransmitter can coexist in astrocytes (Fellin and Carmignoto 2004). For example, multiple mechanisms of release
that are independent on Ca2+ mobilization have been
described for glutamate (Kimelberg et al. 1990; Duan et al.
2003; Ye et al. 2003) and ATP (Cotrina et al. 1998). Despite
the different mechanisms that govern the release of gliotransmitters, all these studies support the view that astrocytes
by releasing chemical transmitters play a fundamental role in
the modulation of synaptic transmission and neuronal
function.
Coincidence detection of astrocytic and neuronal signals at
single synapses
Using Ca2+ uncaging together with minimal stimulation to
activate single synapses, Perea and Araque show that
astrocytes control synaptic transmission at single hippocampal synapses (Perea and Araque 2007). UV uncaging of Ca2+
in single astrocytes causes a transient increase in synaptic
transmission which is due to the pre-synaptic increase in the
probability of release with no change in synaptic potency.
Astrocyte-induced change in synaptic transmission is transient, lasts for less than a minute and is generated by
glutamate released from astrocytes activating pre-synaptic
mGluRs. Most importantly, the transient increase in synaptic
transmission becomes long-lasting when photolytic stimulation of astrocytes is associated with a neuronal post-synaptic
depolarization. Indeed, mild depolarizations of the postsynaptic neurons to )30 mV, that do not modify synaptic
transmission per se, lead to long-term potentiation (LTP) of
synaptic transmission when astrocytes are photostimulated
(Perea and Araque 2007). This elegant study demonstrates
the importance and complexity of astrocytic function at the
tripartite synapse. Ca2+-dependent glutamate release from
astrocytes causes a transient potentiation in synaptic transmission but when this glial signal is coupled to a post-
synaptic depolarization it leads to a previously unrecognized
form of LTP. Whether this astrocyte-mediated form of LTP
occurs during spontaneous and activity-driven Ca2+ oscillations in astrocytes and whether this phenomenon is important
for learning and memory is still unknown. These findings,
together with the observation that Ca2+ signaling in astrocytes is able to sense the level of neuronal activity (Pasti
et al. 1997) and to integrate signals from different synaptic
pathways (Perea and Araque 2005), suggest that astrocyte are
not only signaling cells, but may also contribute to integration and processing of information in the brain (Fig. 3b).
Glutamate release from astrocytes influences network
activity
Spontaneous Ca2+ oscillations in astrocytes occur in vitro
(Nett et al. 2002) and in vivo (Takata and Hirase 2008)
independently from neuronal activity and their function is
still not clear. The observation that spontaneous Ca2+ spikes
in astrocytes correlates in thalamic neurons with the detection
of slow inward currents (SICs) mediated by the NMDA
receptor (Parri et al. 2001), suggests that these spontaneous
Ca2+ signals mediate the release of glutamate from astrocytes
to modulate neuronal excitability. Since then, a number of
studies have investigated the nature of these slow inward
currents and showed that different protocols that stimulate
Ca2+ signaling in astrocytes also increase the frequency of
observation of SICs in neurons. Pharmacological stimulation
(Angulo et al. 2004; Kang et al. 2005; Fellin et al. 2006c;
Kozlov et al. 2006; Nestor et al. 2007; Navarrete and Araque
2008; Shigetomi et al. 2008), single astrocyte stimulation
(Fellin et al. 2004; Perea and Araque 2005; D’Ascenzo et al.
2007), single neuron depolarization (Navarrete and Araque
2008) and extracellular stimulation of neuronal afferents
(Fellin et al. 2004; D’Ascenzo et al. 2007), all resulted in
Ca2+ elevations in astrocytes and detection of SICs in nearby
neurons. Furthermore, these studies demonstrated that glutamate released from glia generates SICs by activating a
particular set of NMDA receptors located at extrasynaptic
sites and containing preferentially the NR2B subunit (Fellin
et al. 2004). When recorded in current-clamp, SICs can
cause suprathreshold depolarization and thus trigger action
potential firing in neurons (Fellin et al. 2006a). Most
importantly, SICs occur with a high degree of synchronization in different neurons (Angulo et al. 2004; Fellin et al.
2004; Kozlov et al. 2006). When two neurons were simultaneously recorded in voltage clamp and were <100 lm
apart, SICs occur with a high temporal correlation in the two
cells, while no synchronous SICs were recorded when the
two neurons were more than 100 lm apart. These electrophysiological results are confirmed by confocal Ca2+ imaging
experiments showing that SICs occur synchronously in small
groups (from 2 to more than 10) of contiguous neurons
(Fellin et al. 2004). Several studies and different groups
described these currents in various brain regions including
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Glial regulation of neuronal activity | 539
the thalamus (Parri et al. 2001), the cortex (Ding et al.
2007), the hippocampus (Angulo et al. 2004; Fellin et al.
2004; Cavelier and Attwell 2005; Kang et al. 2005; Perea
and Araque 2005; Nestor et al. 2007; Shigetomi et al. 2008),
the nucleus accumbens (D’Ascenzo et al. 2007) and the
olfactory bulb (Kozlov et al. 2006). While it could be argued
that the majority of these studies were performed using
artificial means to stimulate Ca2+ signaling into astrocytes
(flash photolysis, pharmacological stimulation), it must be
noted anyway that SICs were first described to be correlated
with endogenous, spontaneous oscillations in thalamic slices
(Parri et al. 2001).
A recent study generated transgenic mice in which a Gqcoupled receptor is expressed selectively into astrocytes and
is activated specifically by an exogenous ligand (Fiacco et al.
2007). Using this approach, the authors could reliably induce
long-lasting (>1 min) Ca2+ plateaus in the majority of
hippocampal astrocytes, but failed to detect glutamate release
from astrocytes and, as a consequence, SICs in neurons.
Nevertheless, when the authors generate faster (10–20 s)
Ca2+ transient in astrocytes by means of IP3 uncaging they
could induce glutamate release from astrocytes and measure
its effect on neuronal excitability (Fiacco et al. 2007),
suggesting that the duration of Ca2+ oscillations may be
crucial to determine or not the release of glutamate from
these glia. A very recent study (Shigetomi et al. 2008)
confirms and expands this hypothesis. When agonists for
P2Y1 and PAR-1 receptors are applied to the slice, they have
no significant effect on the membrane properties of neurons
but generate Ca2+ signals in astrocytes with significantly
different time courses and kinetics. Electrophysiological
recordings reveal that only activation of PAR-1 receptors and
not of P2Y1 receptors is associated with glutamate release
and SICs generation in neurons, demonstrating that Ca2+
signaling in astrocytes is not an all-or-none phenomenon but
that the duration and kinetics of the Ca2+ transients in
astrocytes are key factors controlling the release of gliotransmitters (Shigetomi et al. 2008). Moreover, a different
study confirms that activation of PAR-1 receptors triggers
glutamate release from astrocytes which depolarizes neurons
by activating NMDA receptors, but shows that PAR-1
receptor-dependent glutamate release from astrocytes causes
a tonic depolarization and no SICs in neurons (Lee et al.
2007). These findings raise the potential that there are yet
unknown mechanisms that control the quantity of glutamate
released or the mechanism of Ca2+-dependent release from
astrocytes.
Altogether these studies show that Ca2+ signaling in
astrocytes is a complex phenomenon and that Ca2+ increases
of specific kinetics and duration result in glutamate release
from astrocytes and the generation of SICs in nearby
neurons. Moreover, by activating NR2B-containing NMDA
receptors, glutamate release from glia can generate synchronous depolarization and action potential firing in small
groups of contiguous neurons. Recently, it has been
suggested that this form of astrocyte-to-neuron communication could act as a source of runaway excitation in seizure
pathologies and a few studies have been performed to
address this hypothesis (Kang et al. 2005; Tian et al. 2005;
Fellin et al. 2006a). While Ca2+ oscillations in astrocytes
and, as a consequence, SICs in neurons are found to be
increased in a number of in vitro models of epilepsy (Tian
et al. 2005; Fellin et al. 2006a), pharmacological inhibition
of SICs does not prevent the generation of epileptiform
activity but significantly attenuates the ictal, seizure-like
event (Fellin et al. 2006a). These data suggest that glutamate
released from astrocytes, although not necessary for the
generation of epileptiform activity, may act as a feed-forward
mechanism to enhance neuronal excitation during seizure
pathologies (Fellin and Haydon 2005; Tian et al. 2005).
Besides their role in the modulation of neuronal excitability,
it has been suggested that SICs, by activating NR2Bcontaining NMDA receptors, could also generate signaling
messages for cellular death (Carmignoto and Fellin 2006).
Indeed, the selective activation of NR2B-containing NMDA
receptors is linked to the activation of cellular death
pathways (Hardingham et al. 2002), raising the possibility
that under specific conditions astrocytes could modulate this
signaling pathway. A recent study confirms this hypothesis
and demonstrates that pharmacological attenuation of this
astrocytes-to-neuron signaling pathway provides significant
protection from the neuronal death that follows a brain insult
such as status epilepticus (Ding et al. 2007).
TNFa released by astrocytes mediates synaptic scaling
When neurons are subjected to prolonged periods of altered
synaptic activity, they scale their output to compensate for
the global change in network activity (Davis 2006; Rich and
Wenner 2007). All synapses are potentiated or depressed
proportionally and all synapses are scaled independently
from their initial strength. This form of plasticity tends to
stabilize the neuronal network in face of a perturbation and is
called homeostatic plasticity to distinguish it from Hebbian,
synapse-specific forms of plasticity such as LTP (Turrigiano
and Nelson 2004; Turrigiano 2007). A typical protocol
consists of blocking neuronal activity by prolonged
incubation of neuronal cultures with tetrodotoxin and then
measuring the effect of this treatment on miniature excitatory
post-synaptic currents (mEPSCs) (Turrigiano et al. 1998).
Under these conditions, the amplitude distribution of
mEPSCs is scaled up and for this reason this form of
homeostatic plasticity is usually named ‘synaptic scaling’. In
cortical and hippocampal pyramidal cells, one mechanism by
which synapses adapt to the overall decreased activity and
become stronger is by increasing the number of alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptors in the post-synaptic membrane (Rich and Wenner
2007; Turrigiano 2007). A recent study demonstrates that the
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540 | T. Fellin
release of the cytokine TNFa from astrocytes contributes to
this form of plasticity (Stellwagen and Malenka 2006). By
combining the use of transgenic mice with a pharmacological
approach, the authors show that TNFa mediates the increase
in synaptic strength that follows a prolonged incubation of
the neuronal culture with TTX. In contrast, TNFa signaling
is not required for other forms of plasticity such as LTP and
long-term depression. Using a clever approach utilizing
mixed cultures from wild-type (WT) and TNFa knock-out
mice, the authors demonstrate that astrocytes are the primary
source of this pro-inflammatory cytokine (Stellwagen and
Malenka 2006). When neurons from WT or TNFa knock-out
mice are plated with WT astrocytes the increase in mEPSCs
amplitude in response to TTX incubation is normally
observed. However, when WT neurons are plated together
with astrocytes from TNFa knock-out mice, no homeostatic
increase in mEPSCs amplitude is observed. Most importantly, astrocytic TNFa signaling is involved only in the
scale-up of synapses following TTX treatment, while it has
no role in the scaling down of synapses that follows a
prolonged increase in neuronal activity (Stellwagen and
Malenka 2006).
These results demonstrate that the gliotransmsitter TNFa
is the mediator of the specific form of synaptic scaling that
occurs in response to prolonged blockade of neuronal
activity. Glia are thus one of the sensors for homeostatic
regulation and are crucial modulators of neuronal network
activity (Fig. 3b). Nevertheless, a number of exciting questions are still to be addressed. For example, a recent report
shows that TNFa-mediated synaptic scaling is involved in
OD plasticity (Kaneko et al. 2008). After monocular deprivation, neurons in the binocular region of the visual cortex
decrease their response to the closed eye and increase their
responsiveness to the open eye. Using transgenic mice, this
study suggests that the increase in the open eye response is a
homeostatic process mediated by TNFa (Kaneko et al.
2008). Given that astrocytes are a major source of TNFa,
that they respond to visual stimulation and that they are able
to secrete permissive factors for OD plasticity, these results
suggest that astrocytes have the potential to be key elements
in the control of neuronal network function and plasticity
in vivo. Future experiments will investigate how astrocytes
sense the global change in network activity, which are the
molecular mechanisms controlling the release of TNFa and
whether other gliotransmitters are involved in different forms
of homeostatic plasticity.
process of the astrocyte contacting the synapse but where
exactly the sites of release are and whether different
gliotransmitters have different release locations is not clear.
Structural evidences support the view that for some transmitters the release may occur close to the synapse since
glutamate-containing vesicles have been identified in the
astrocytic process facing synaptic structures (Bezzi et al.
2004). Moreover, functional evidence provided by Oliet and
coworkers in the supraoptic nucleus of the hypothalamus
suggests that the astrocytic process contains the site of
release for D-serine (Panatier et al. 2006). Under normal
conditions in this brain region astrocytic processes enwrap
neurons, but during lactation the astrocytic morphology is
drastically changed and astrocytic processes are completely
withdrawn. Using this experimental model, the authors were
able to demonstrate that the astrocytic process releases Dserine into the synaptic cleft to modulate synaptic but not
extrasynaptic NMDA receptors (Panatier et al. 2006). On the
other hand, different studies demonstrate that gliotransmission impact receptors located at extrasynaptic or perisynaptic
sites with little or no effect on synaptic receptors (Araque
et al. 1998; Fellin et al. 2004), raising the possibility that
different transmitters could be released at different locations.
Given that we know very little about the spatial locations
where gliotransmitters are released, it should be remembered
that astrocytes contact neurons not only at synapses, but also
at cell bodies (Peters et al. 1991; Volterra et al. 2002) and
thus it cannot be excluded that part of the signaling between
astrocytic and neuronal cells occurs at these latter locations.
As the coincidence detection of the neuronal and astrocytic
input determines the outcome of synaptic plasticity (Perea
and Araque 2007), understanding the timing of gliotransmission with respect to neurotransmission is of equal
importance. For example, in vivo and in situ we have very
limited information about how in the extracellular space the
concentration profile of most gliotransmitters varies with
time, whether astrocytes are constantly releasing these
molecules, or whether the release is strictly dependent on
the neuronal activity. Nevertheless, for a few gliotransmitters,
as for example, ATP, we do know that astrocytes release it
both tonically and in an activity-dependent way. Constant
release of ATP that is rapidly degraded to adenosine provides
a tonic suppression at hippocampal synapses, while activitymediated ATP release from astrocytes is responsible for
heterosynaptic depression (Pascual et al. 2005).
Is gliotransmission organized in domains?
Gliotransmission: understanding space and time
Given that gliotransmission modulates various aspects of the
neuronal function, understanding where it occurs and the
position of the neuronal receptors involved in this process is
of fundamental importance. It is usually assumed that the
release of chemical transmitters from glia occurs at the
If we restrict our discussion to Ca2+-dependent gliotransmission, where we can monitor Ca2+ which is the stimulus for
transmitter release, the observation that Ca2+ signaling in
astrocytes is organized in functional domains (Fig. 2) would
support the hypothesis of a domain organization for
gliotransmission. Moreover, the existence of at least two
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Glial regulation of neuronal activity | 541
(a)
(b)
Fig. 4 Gliotransmission triggered by spontaneous or activity-evoked
Ca2+ signals may lead to different effects on neuronal networks. (a)
Spontaneous Ca2+ signaling in astrocytes is compartmentalized in
single cells (red line) and thus Ca2+-dependent release of gliotransmitter has the potential to affect only those neuronal structures within
the single-cell astrocytic domain. (b) On the contrary, groups of multiple
astrocytes respond to the same sensory stimulus with Ca2+ elevations
and thus gliotransmission evoked by sensory stimulation is organized
in functional domains (red line) larger than the anatomical ones (black
line) and may affect a much higher number of neuronal structures.
different modes of Ca2+ signaling, spontaneous and
activity-evoked, with distinct spatial patterns suggest that
gliotransmission evoked by spontaneous or activity-driven
oscillations may impact different spatial regions and potentially have different functional roles (Fig. 4). Given that
spontaneous Ca2+ signaling in astrocytes displays a low level
of correlation among different glial cells, one can envision
that intrinsic spontaneous oscillations would cause gliotransmission to impact only the neuronal structures within the
domain of a single astrocyte (Fig. 4a). In contrast, gliotransmission triggered by activity-mediated Ca2+ signals would be
correlated in many more cells (2 to more than 10 different
glial cells, Fig. 2). The number of neurons that can be
influenced by activity-evoked gliotransmission may thus be
up to one order of magnitude higher than that influenced
by gliotransmission driven by spontaneous oscillations
(Fig. 4b).
Besides the different number of neurons affected, these
two modes of signaling could lead to profound differences
also in the effect of gliotransmitters on neuronal function. For
example, glutamate release evoked by spontaneous oscillations by activating pre-synaptic mGluRs would have a high
probability of generating short- rather than long-term plasticity (Perea and Araque 2007). Indeed, spontaneous Ca2+
oscillations occur independently of neuronal activity and thus
the probability of having release from astrocytes coincident
with a post-synaptic depolarization would be low. In contrast,
activity-dependent release from astrocytes would have a
higher chance of generating long- rather than short-term
plasticity given that neuronal activity would cause both Ca2+
signals in astrocytes and neuronal depolarization. Furthermore, it must be remembered that most activity-evoked
astrocytic responses occur with a delay of a few seconds with
respect to the neuronal responses (Wang et al. 2006;
Schummers et al. 2008). This suggests that gliotransmission
would lead to a long- rather than short-term effect only if the
neuronal stimulus that determines the astrocytic response
lasts for more than a couple of seconds or if the first neuronal
stimulus is followed by a second neuronal input that
generates post-synaptic depolarization during gliotransmission. Activity-driven release of gliotransmitters could thus
contribute to the refinement of neuronal connectivity during
activity-dependent plasticity, while gliotransmission evoked
by spontaneous oscillations would provide an activityindependent feedback to synapses.
Concluding remarks
It is now clear that astrocytes are more than the traditional
supportive cells providing only structural and metabolic
support to neurons. In vivo experiments show that astrocytes
are endowed with an intrinsic Ca2+ excitability (Takata and
Hirase 2008) and that they can respond to increased neuronal
activity with augmented Ca2+ signaling (Wang et al. 2006;
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542 | T. Fellin
Schummers et al. 2008). Astrocytes are involved in key
functions of the brain such as the control of cerebral blood
flow (Zonta et al. 2003; Mulligan and MacVicar 2004;
Takano et al. 2006), synapse formation and stabilization
(Christopherson et al. 2005) and are crucial element for the
structural plasticity of the synapse (Haber et al. 2006).
Additionally, they release chemical transmitters to modulate
synaptic transmission and neuronal excitability (Parpura
et al. 1994; Bezzi et al. 1998; Kang et al. 1998; Pascual
et al. 2005; Panatier et al. 2006). The results discussed in
this review suggest that gliotransmission regulates fundamental aspects of neuronal function. By releasing glutamate,
astrocytes can influence Hebbian plasticity at single synapses
(Perea and Araque 2007) and generate coordinated activity in
groups of neurons (Fellin et al. 2004), while, by releasing
TNFa, they mediate global synaptic scaling of neuronal
networks (Stellwagen and Malenka 2006). Although these
recent studies give examples of the potential of astrocytes to
control neuronal excitability and synaptic plasticity, the
importance of this astrocyte-to-neuron communication in
brain physiology and pathology in vivo is still largely
unknown. Understanding how all the different effects
generated by distinct gliotransmitters integrate with one
another, which are the mechanisms controlling the release of
different gliotransmitters, which are the neuronal signals
activating diverse pathways of gliotransmission, and what is
the importance of these different pathways in brain physiology and pathology represents the current challenge in the
field. The development of transgenic mouse models bearing
specific mutations in different intracellular signaling pathways together with the use of physiological techniques for
the study of neuronal function in vivo will represent a valid
model for addressing some of these questions.
Acknowledgments
This work was supported by the Italian Institute of Technology. I am
grateful to F. Benfenati, M. D’Ascenzo, R. Fellin, R. R. Gainetdinov, and P. G. Haydon for critical reading of this manuscript and
helpful comments.
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Ó 2008 The Author
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