Tài liệu Báo cáo khoa học: Synchronization of Ca2+ oscillations: involvement of ATP release in astrocytes pdf

MINIREVIEW
Synchronization of Ca
2+
oscillations: involvement of ATP
release in astrocytes
Schuichi Koizumi
Department of Pharmacology, Faculty of Medicine, University of Yamanashi, Japan
Introduction
Glia, Greek for ‘glue’, was discovered by Rudolph
Virchow, a German anatomist, in the mid-nineteenth
century. The name reflects the original view that glia
played merely a structural or supportive role for neu-
rons. Glial cells, especially astrocytes, are much more
than ‘glue’ or merely quiescent, and display their own
set of activities. They can receive inputs, assimilate
information, and send instructive chemical signals
both to neurons and to other neighboring cells.
Astrocytic activities may be assessed by an observed
increase in the intracellular Ca
2+
concentration
([Ca
2+
]
i
), using fluorescent Ca
2+
imaging techniques.
Astrocytes show transient increases in [Ca
2+
]

i
(Ca
2+
transients) that spread into adjacent astrocytes and
neurons to form synchronous Ca
2+
oscillations or
Ca
2+
waves. Initially, such Ca
2+
events were believed
Keywords
astrocytes; ATP; Ca
2+
release;
gliotransmitter; neuron–glia; neurons; P2
receptors
Correspondence
S. Koizumi, Department of Pharmacology,
Faculty of Medicine, University of
Yamanashi, 1110 Shimokato, Chuo,
Yamanashi 409-3898, Japan
Fax: +81 55 273 6739
Tel: +81 55 273 9503
E-mail:
(Received 25 May 2009, revised 25 August
2009, accepted 28 September 2009)
doi:10.1111/j.1742-4658.2009.07438.x
Glial cells, especially astrocytes, are not merely supportive cells, but are

important partners to neighboring cells, including neurons, vascular cells,
and other glial cells. Although glial cells are not excitable in terms of
electrophysiology, they have been shown to generate synchronized Ca
2+
transients (Ca
2+
oscillations) through mechanisms of chemical coupling.
Until recently, Ca
2+
transients in astrocytes were thought to be totally
dependent on neuronal activities, because astrocytes express a large vari-
ety of receptors for neurotransmitters and surround almost all synapses
at which neurotransmitters are spilled over to stimulate astrocytes. In
addition, however, astrocytes have been shown to release diffusible sub-
stances, so-called ‘gliotransmitters’, and Ca
2+
transients in astrocytes are
therefore also triggered by astrocytic activities, leading to propagation of
Ca
2+
transients or Ca
2+
waves. In these processes, the gliotransmitter
ATP and activation of P2Y receptors play central roles. Interestingly,
astrocytes evoke Ca
2+
transients when neurons are not present, suggest-
ing that astrocytes themselves can initiate and control Ca
2+
transients.

Astrocytic Ca
2+
transients are observed even in vivo, through mechanisms
of chemical coupling by gliotransmitters, but they are less frequent and
synchronous than those in vitro. Although we have not yet clarified their
significance in the central nervous system, astrocytic Ca
2+
transients are
dramatically affected by pathological conditions, suggesting that, in addi-
tion to physiological events, they might be closely involved in disorders
in the central nervous system.
Abbreviations
[Ca
2+
]
i
, intracellular Ca
2+
concentration; SIC, slow-inward current; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein
receptor; TTX, tetrodotoxin.
286 FEBS Journal 277 (2010) 286–292 ª 2009 The Author Journal compilation ª 2009 FEBS
to be solely triggered by neurotransmitters that are
spilled over at the synapses. However, astrocytes
themselves integrate and form synchronized Ca
2+
transients by mechanisms of chemical coupling. In
this, extracellular ATP and activation of P2 receptors
play central roles. In addition, although rapid neuro-
transmission was believed to be restricted solely to
neuron–neuron communication, it has been found to

include glial cells [1,2]. Evidence suggests that such
Ca
2+
-mediated extracellular signaling between astro-
cytes and neurons could be involved in the regulation
of synaptic transmission both in physiological and in
pathophysiological conditions.
In this minireview, the mechanisms underlying syn-
chronous Ca
2+
transients in astrocytes are summarized
from the viewpoint of chemical coupling by ATP.
Using this coupling, astrocytes regulate neurons and
vice versa. Neuron–glia communication appears to be
accentuated in pathophysiological conditions such as
epilepsy. Thus, the involvement of astrocytic Ca
2+
transients in epileptiform discharge in neurons is also
discussed.
Astrocytic Ca
2+
transients in vitro
The development of video imaging techniques has
allowed us to observe dynamic spatiotemporal changes
in [Ca
2+
]
i
in neurons and glial cells simultaneously.
Unlike neurons, astrocytes do not produce action

potentials, and thus they were thought to be quiescent.
However, they have since been found to be busy or
noisy in terms of ‘Ca
2+
excitability’. About 20 years
ago, elevations in [Ca
2+
]
i
in individually cultured
astrocytes in response to neurotransmitters were first
reported [3]. After initial observations, it became
apparent that many neurotransmitters stimulate [Ca
2+
]
elevations in astrocytes by activating specific receptors
expressed on these cells. Astrocytes express a wide
range of receptors for different neurotransmitters, sur-
round almost all synapses, and therefore respond to
neurotransmitters spilled over at synapses when
neurons are activated [1]. Thus, Ca
2+
transients in
astrocytes were initially thought to be totally depen-
dent on neurons (Fig. 1A).
Subsequently, it was demonstrated that these Ca
2+
transients could, in turn, stimulate the release of chem-
ical transmitters from astrocytes, which mediates com-
munication between astrocytes (Fig. 1Ab) [3,4] and

even neurons (Fig. 1Ac) [5]. For some years, astrocytic
Ca
2+
waves have been thought to propagate via gap
junctions [6], with the internal messenger inositol 1,4,5-
trisphosphate being the diffusible substance that
induces Ca
2+
release in neighboring cells. However,
Ca
2+
waves are propagated between astrocytes even
when the cells do not have an absolute requirement for
functional contact with each other directly, and the
extent and direction of the Ca
2+
wave propagation are
significantly influenced by movement of the extracellu-
lar medium [7]. These more recent reports suggest that
substances released from astrocytes can activate recep-
tor systems on astrocytes, evoking the release of addi-
tional substances, and thus producing a synchronized
propagating Ca
2+
wave of activity. In 1999, Guthrie
et al. [7] demonstrated that astrocytes release ATP,
which is responsible for the spreading of Ca
2+
tran-
sients with a slight synchronization (Fig. 1Ab). The

spreading of Ca
2+
transients in astrocytes appears to
be mediated by chemical coupling by ATP, for the fol-
lowing reasons. First, ATP is released from astrocytes
during Ca
2+
wave propagation [7,8]. Second, the prop-
agation can be reduced or even abolished by a puriner-
gic antagonist [5,7–9] or the ATP-degrading enzyme
apyrase [5,7]. Third, visualization of the release of
ATP demonstrates that the velocity of ATP release
correlates well with that of the Ca
2+
wave in astro-
cytes [5]. All of these findings suggest that the extra-
cellular molecule ATP could be a primary signal for
the Ca
2+
wave propagation, and highlight the impor-
tance of ATP in cross-talk among astrocytes and even
other cell types in the central nervous system
(Fig. 1Ac). Such glial chemical couplings are termed
‘gliotransmissions’, and ATP serves a central role as a
gliotransmitter.
Now we understand that astrocytes receive and
respond to neurotransmitters, and release gliotrans-
mitter ATP to form synchronized and spreading
Ca
2+

transients. However, it should be noted that
astrocytes themselves evoke the propagating Ca
2+
transients. As shown in Fig 1Ba, which represents
changes in [Ca
2+
]
i
in the neuron–astrocyte cocultures,
astrocytes and neurons show Ca
2+
oscillations with
different frequency and temporal patterns; that is,
Ca
2+
oscillations in astrocytes are less frequent and
synchronous than those in neurons. Importantly, the
Ca
2+
transients in astrocytes do not disappear when
neuronal Ca
2+
oscillation is inhibited by tetrodotoxin
(TTX) (Fig. 1Ba). In addition, astrocytes show spon-
taneous Ca
2+
transients even when they have been
purified and cultured without neurons (Fig. 1Bb).
These findings suggest that astrocytes can initiate the
spontaneous Ca

2+
transients by a neuronal activity-
independent mechanism. Such Ca
2+
transients were
almost abolished by apyrase (Fig. 1B) and P2 recep-
tor antagonists, suggesting that extracellular ATP and
activation of P2 receptors are responsible for the
spontaneous Ca
2+
events.
S. Koizumi Astrocytic Ca
2+
oscillations and neuronal activities
FEBS Journal 277 (2010) 286–292 ª 2009 The Author Journal compilation ª 2009 FEBS 287
Mechanisms of ATP release from
astrocytes
The P2 receptors responsible for increases in [Ca
2+
]
i
in
astrocytes are well characterized, and G-protein-cou-
pled P2Y1 and P2Y2 receptors have been shown to
play central roles in the event (Fig. 2B). However, the
mechanism underlying the release of ATP from astro-
cytes is controversial and a still matter of debate
(Fig. 2B). With regard to the release of glutamate,
astrocytes express soluble N-ethylmaleimide-sensitive
factor attachment protein receptors (SNAREs), have a

vesicular structure expressing the vesicular glutamate
transporters, and release glutamate in a Ca
2+
-depen-
dent and SNARE-dependent manner [10]. These find-
ings strongly suggest that exocytotic machinery is
involved in glutamate release in astrocytes, although
nonvesicular mechanisms for glutamate release have
also been proposed. In contrast, the mechanisms
underlying the release of ATP from astrocytes are less
Astrocytes
ATP
ATP
dF/F0
=0.2
10 s
3
4
TTX
Apyrase
1
2
Apyrase
5
6
Purified astrocytes
Neuron–astrocyte coculture
Neurons
Astrocytes
a

ATP
ATP
Neurons
Astrocytes
b
ATP
ATP
Astrocytes
Neurons
c
a
b
c
A
B
Initiator
Fig. 1. Synchronized Ca
2+
transients in astrocytes and neurons. (A) Cartoon of neuronal activity-dependent Ca
2+
transients in astrocytes. (a)
When neurotransmitters such as glutamate are released from nerve terminals, some are spilled over and stimulate adjacent astrocytes (peri-
synaptic astrocyte) to evoke Ca
2+
transients in the cell. (b) If neurons are excessively excited, perisynaptic astrocytes causes frequent Ca
2+
transients or Ca
2+
oscillations, followed by the spreading of Ca
2+

transients in adjacent astrocytes to form intercellular Ca
2+
waves by a
mechanism of chemical coupling mediated by ATP. In both cases, an increase in [Ca
2+
]
i
is driven by neuronal activities. (c) Astrocytic Ca
2+
transients also affect neuronal activities through the gliotransmitter ATP. (B) Neuronal activity-independent Ca
2+
transients in astrocytes. (a)
Neuronal Ca
2+
oscillations seen in the hippocampal neurons (blue traces shown as 3 and 4) are highly synchronous and are inhibited by TTX.
Adjacent astrocytes (red traces shown as 1 and 2) also show slower and less synchronous Ca
2+
oscillations. However, the synchronous
Ca
2+
oscillations in astrocytes are unaffected even when neuronal activities are inhibited by TTX, suggesting that astrocytes have mecha-
nism(s) by which they form neuronal activity-independent Ca
2+
transients. (b) Astrocytes reveal synchronous Ca
2+
transients (red traces 5
and 6) when neurons are not present (purified astrocytes). Astrocytic Ca
2+
oscillations seen in the presence of TTX or in purified astrocytes
were abolished by the ATP-degrading enzyme apyrase. (c) Schematic cartoon of neuronal activity-independent astrocytic Ca

2+
oscillations.
One or some initiator astrocyte(s) release ATP, and this is followed by ATP-dependent Ca
2+
transients that propagate into adjacent
astrocytes.
Astrocytic Ca
2+
oscillations and neuronal activities S. Koizumi
288 FEBS Journal 277 (2010) 286–292 ª 2009 The Author Journal compilation ª 2009 FEBS
well understood. The release of ATP is reduced by
inhibitors of several anion channels [11,12], ATP-bind-
ing cassette proteins or cystic fibrosis transmembrane
conductance regulator [13], gap junctions [14], and
P2X7 receptors, suggesting the involvement of multiple
pathways in the release. In addition to these, the
release of ATP is partly dependent on Ca
2+
[15] and
SNARE proteins [16], and astrocytes possess vesicles
that contain ATP [16,17]. Inhibition of ATP release by
vesicular ATPase inhibitors has also been reported
[17]. Interestingly, Pascual et al. (2005) [18] generated
inducible transgenic mice that express a dominant-neg-
ative SNARE domain selectively in astrocytes to block
the exocytotic events in astrocytes. Using the trans-
genic mice, they demonstrated that astrocytes released
ATP through a mechanism of exocytosis, and that the
astrocytic ATP and its metabolite adenosine tonically
suppressed synaptic transmissions. These results

strongly suggest that astrocytes should release ATP
through a mechanism of exocytosis, which would be a
key event for neuron–astrocyte communication. How-
ever, we still did not know which molecules transport
ATP into astrocytic vesicles. Recently, this question
has been answered. Sawada et al. (2008) [19] demon-
strated that SLC17A9 or vesicular nucleotide trans-
porter, a novel member of an anion transporter family,
functions as a vesicular nucleotide transporter, and is
essential for the storage of nucleotides within vesicles.
Importantly, SLC17A9 is expressed in astrocytes.
These findings suggest that the mechanisms of ATP
release could also include exocytosis, although the nat-
ure of the signals released from astrocytes may vary
with varying physiological and pathological conditions
[17]. It is important to elucidate the mechanisms by
which astrocytes release ATP in response to distinct
stimuli, as this will further clarify the mechanisms
underlying the synchronized Ca
2+
transients.
Astrocytic Ca
2+
waves in vivo
With the recent development of multiphoton micros-
copy, we can observe astrocytic Ca
2+
transients in vivo.
Hirase et al. [20] were the first to analyze changes in
[Ca

2+
]
i
in cortical astrocytes from living, anesthetized
rats using this technique. Over 60% of the imaged
astrocytes showed spontaneous Ca
2+
transients with
complex spatiotemporal patterns. The spontaneous
Ca
2+
transients in vivo were very complex and occurred
with a relatively low frequency under basal conditions.
They showed a limited degree of correlation with
nearby astrocytes when compared with those seen
in vitro [20]. However, like Ca
2+
transients in vitro,
astrocytic Ca
2+
transients in vivo occurred, in large
part, intrinsically rather than being neuronal activity-
driven, although ATP-mediated chemical coupling was
not demonstrated [21]. However, a recent in vivo Ca
2+
imaging experiment by Nimmerjahn et al. (2009) [22]
demonstrated that anesthetic agents greatly decreased
Ca
2+
responses in glial cells and that, in awake behav-

ing mice, Ca
2+
responses in cerebellar Bergmann glia
(radial astrocytes) were more frequent and contained
ATP-mediated components. The less frequent chemical
coupling in vivo might result, in part, from the fact that
the activity of the ATP-degrading enzyme ectonucleo-
tidases is higher in vivo or in slice preparations than in
primary cultures in vitro [18,23]. Astrocytic Ca
2+
tran-
sients in vivo also include a component that is depen-
dent on neuronal activities. In the mouse or ferret,
whisker [24], limb [25] and visual stimulation [26] causes
more frequent Ca
2+
transients in astrocytes in the bar-
rel, the primary somatosensory cortex, and the visual
cortex, respectively. These Ca
2+
transients in astrocytes
were delayed by a few seconds as compared with the
Astrocyte
Exocytosis
Cl
–
channels
P2X7 receptors
P2Y1,P2Y2
Maxi-anion

channels
Connexin/pannexin
hemichannels
N
Gq
PLC
ATP, ADP, UTP
ER
Ca
2+
C
Ins(1,4,5)P
3
Ins(1,4,5)P
3
-R
A
B
Fig. 2. P2 receptors and secretory pathways of ATP in astrocytes.
(A) The predominant P2 receptors that produce Ca
2+
transients in
astrocytes are P2Y1 and P2Y2 receptors, both of which are coupled
with Gq–phospholipase C (PLC), and activation of which results in
the formation of Ins(1,4,5)P
3
, leading to Ca
2+
release from Ca
2+

stores. (B) Multiple pathways for the release of ATP. Hemichannels
of connexin or pannexin, maxi-anion channels, P2X7 receptors and
Cl
)
channels are pathways through which ATP can flow. In addi-
tion, the existence of exocytotic ATP is also suggested. ER, endo-
plasmic reticulum.
S. Koizumi Astrocytic Ca
2+
oscillations and neuronal activities
FEBS Journal 277 (2010) 286–292 ª 2009 The Author Journal compilation ª 2009 FEBS 289
neuronal responses [24,26], and nearly correlated with
the strength of the sensory stimulation. Thus, neuronal
activities also affect astrocytic Ca
2+
transients. More
importantly, the application of bicuculine, an antago-
nist of 4-aminobutyrate A receptor [20], or picrotoxin
[27] increases neuronal activity by triggering epileptic-
like discharges, which subsequently result in a great
increase in Ca
2+
transients that are often propagated
into nearby astrocytes [20]. Thus, neuronal activity-dri-
ven Ca
2+
oscillation occurs synchronously in multiple
astrocytes, and seems to be accentuated by pathological
activities of neurons such as epileptiform discharges.
Pathology and Ca

2+
transients in
astrocytes
Ca
2+
waves in astrocytes propagate into neurons and
affect the excitability of neurons via the release of
neuroactive gliotransmitters such as ATP and gluta-
mate, and affect synaptic transmission [5,23]. Both
ATP and glutamate are gliotransmitters through which
astrocytes can actively regulate synaptic transmission.
ATP differs from glutamate in that it inhibits rather
than potentiates synaptic transmission. Thus, we
hypothesize that the opposing actions of astrocytic glu-
tamate and ATP represent a means by which astro-
cytes can dynamically modulate neuronal activity by
releasing distinct transmitters, which can either excite
or inhibit synaptic transmission (Fig. 3B, left). There-
fore, one can easily imagine that dysfunctional astro-
cytes in certain pathological conditions could result in
an imbalance in neuronal excitability, leading to excess
neuronal excitation, such as in epilepsy (Fig. 3A,
right). Epileptic seizures are sudden uncontrolled
attacks of a convulsive or a nonconvulsive nature asso-
ciated with unusually intense neuronal firings.
Although epilepsy is a neurocentric disorders, the
involvement of astrocytes in its pathophysiology is the
Neurons
Astrocytes
ATP

Neurons
SIC
SIC
Astrocytes
ATP
ATP/ado
ATP
ATP
Reactive
astrocytes
SIC
SIC
SIC
SIC
SIC
-
+
Neurons
glu
glu
glu
glu
glu
glu
glu
Epileptiform dischar
g
e
glu
Neurons

TP/ado
-
+
glu
ATP
ATP
Epileptiform discharge
A
B
A
Fig. 3. Neuronal activities or epileptiform discharges induced by astrocytic Ca
2+
transients. (A) Ca
2+
transients in perisynaptic astrocytes
result in the release of multiple gliotransmitters, i.e. ATP (or its metabolite adenosine, ado) and glutamate (glu). Astrocytic ATP inhibits neu-
ronal excitation, whereas glutamate increases it. If one of these dual effects of astrocytes is impaired, adjacent neurons will cause excess
excitability, owing to an imbalance of inhibitory and excitatory modulation, leading to epileptiform discharges in neurons. (B) Release of gluta-
mate induced by astrocytic Ca
2+
transients induces SICs in neighboring neurons. Reactive astrocytes show increased Ca
2+
transients and
release of glutamate, subsequently inducing synchronous SICs in adjacent neuronal networks. This synchronization of SICs is able to cause
epileptiform discharges in neurons.
Astrocytic Ca
2+
oscillations and neuronal activities S. Koizumi
290 FEBS Journal 277 (2010) 286–292 ª 2009 The Author Journal compilation ª 2009 FEBS
subject of growing interest and, in fact, the functions

of several astrocyte-specific molecules are associated
with epilepsy-like firing in neurons [28]. A spatially
restricted seizure focus in the brain can be identified
for epilepsies acquired after head trauma, tumor, or
other severe focal insults to the brain, when astrocytes
often become reactive. Reactive astrocytes change in
their abilities to release, take up and metabolize glio-
transmitters, which would cause unusual excitation of
adjacent local neuronal networks [28]. Recently, it was
proposed that slow-inward currents (SICs) recorded in
the hippocampal neurons are caused by astrocytic glu-
tamate [29,30] (Fig. 3B). Although astrocyte-induced
SICs are not epileptiform bursts as such (Fig. 3B, left),
their synchronization is closely associated with the for-
mation of ictal bursts. Astrocytic Ca
2+
oscillation and
the subsequent glutamate release are key events in the
synchronization of SICs [31]. As shown in the right
panel of Fig. 3B, reactive astrocytes increase the
release of glutamate by facilitating Ca
2+
oscillations in
response to the gliotransmitter ATP (or glutamate),
and generate synchronous SICs in small groups of con-
tiguous neurons, followed by epilepsy-like firings [28].
Interestingly, several antiepileptic agents, including val-
proate, gabapentin, and phenytoin, reduce astrocytic
Ca
2+

oscillations, thereby leading to inhibition of the
synchronization of SICs [30]. Thus, Ca
2+
transients in
reactive astrocytes could be closely related to the
observed pathophysiology of epilepsy and could be
therapeutic targets for the treatment of epilepsy or,
potentially, for other brain disorders.
Conclusion and perspective
Astrocytes show synchronous Ca
2+
transients by
mechanisms of chemical coupling that are mainly
mediated by ATP. Asastrocytic Ca
2+
transients are,
in part, dependent on neuronal activities, excess exci-
tation of neurons results in highly frequent and prop-
agating Ca
2+
transients in adjacent multiple
astrocytes, which in turn send feedback signals to
neurons and control their excitation. These neuron–
astrocyte communications mediated by astrocytic
Ca
2+
transients are accentuated in pathological con-
ditions, suggesting the involvement of astrocytic Ca
2+
transients in brain disorders, including epileptic sei-

zures. Interestingly, astrocytes also show spontaneous
Ca
2+
transients that are independent of neuronal
activities. Thus, astrocytes themselves have the ability
to produce their own Ca
2+
transients, and therefore
might control neuronal activities or synaptic transmis-
sions through a mechanism independent of neurons.
The physiological and pathophysiological significance
of the spontaneous Ca
2+
transients in astrocytes
remains unknown. Clarification of the detailed mecha-
nisms underlying the spontaneous Ca
2+
transients in
astrocytes, especially those occurring in vivo, would
shed light on this issue and further our understanding
of the neuron–glia interaction.
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