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Astroglial cradle in the life of the synapse
Alexei Verkhratsky1,2,3 and Maiken Nedergaard4
1
Faculty of Life Sciences, University of Manchester, Manchester, UK
Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
3
University of Nizhny Novgorod, Nizhny Novgorod 603022, Russia
4
Division of Glia Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester
Medical School, Rochester, NY 14580, USA
2
rstb.royalsocietypublishing.org
Review
Cite this article: Verkhratsky A, Nedergaard
M. 2014 Astroglial cradle in the life of the
synapse. Phil. Trans. R. Soc. B 369: 20130595.
http://dx.doi.org/10.1098/rstb.2013.0595
One contribution of 23 to a Theme Issue
‘Brain circuitry outside the synaptic cleft’.
Subject Areas:
neuroscience
Keywords:
astroglia, synapse, astroglial cradle,
synaptogenesis, neurotransmission,
potassium buffering
Authors for correspondence:
Alexei Verkhratsky
e-mail: [email protected]
Maiken Nedergaard
e-mail: [email protected]
Astroglial perisynaptic sheath covers the majority of synapses in the central
nervous system. This glial coverage evolved as a part of the synaptic structure
in which elements directly responsible for neurotransmission (exocytotic
machinery and appropriate receptors) concentrate in neuronal membranes,
whereas multiple molecules imperative for homeostatic maintenance of the
synapse (transporters for neurotransmitters, ions, amino acids, etc.) are shifted
to glial membranes that have substantially larger surface area. The astrocytic
perisynaptic processes act as an ‘astroglial cradle’ essential for synaptogenesis,
maturation, isolation and maintenance of synapses, representing the fundamental mechanism contributing to synaptic connectivity, synaptic plasticity
and information processing in the nervous system.
1. Multiple components of the central synapse
The power of the brain lies in the intercellular connections; some tens of trillions of
these connections create the neural web that is the substrate for information processing. The connectivity of neural networks is immensely plastic and it is constantly
remodelled under the influence of the environment and experience; this remarkable plasticity underlies learning. Intercellular connections in the nervous system
are represented by chemical and electrical synapses, with the former predominantly established between neurons and the latter between neuroglia. Chemical
transmission in the brain is not confined to synapses, it also operates in a
‘volume transmission’ mode when neurotransmitters diffuse through interstitial
space, finding their multiple targets between neurons and neuroglial cells.
Synaptic structures evolved over the last approximately 600 million years,
after the first diffuse nervous system appeared in primitive animals such as
hydras and comb jellies; this first nervous system was composed from cells of
a single cell type, the neurons, which establish a neuronal net through synaptic
contacts. Subsequent evolution of the nervous system progressed by the way of
great diversification and specialization of cells. The first glial-like cells emerged
in nematodes, they became specialized in annelids and attained a high degree
of morphological and functional heterogeneity in arthropods. In basal chordates, the new type of glial cells, the radial glia, replaced parenchymal glial
cells, which signalled an advent of layered organization of the central nervous
system (CNS). Increase in the size of the CNS instigated re-emergence and diversification of astrocytes and appearance of myelin [1]. The brain and the spinal cord
of mammals contain hundreds of distinct types of neurons and many types of
neuroglia. Similarly, there are many types of synapses established between neuronal terminals and effector organs in the periphery or between neuronal terminals
and other neurons and between neurons and some NG2 glial cells [2] in the CNS
as well as in sympathetic ganglia or enteric plexuses.
Synapses in the CNS are composed of several distinct components (figure 1),
which include (i) the presynaptic terminal, (ii) the postsynaptic element that can
be represented, for example, by the dendritic spine, (iii) the perisynaptic process
of the astrocyte, (iv) the process of a neighbouring microglial cell that periodically
contacts the synaptic structure and (v) the extracellular matrix (ECM), which is
present in the synaptic cleft and also extends extra-synaptically. The concept of
this multi-partite synaptic assembly evolved over a recent decade, when it
became clear that complex multidirectional relations exist between all the
& 2014 The Author(s) Published by the Royal Society. All rights reserved.
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presynaptic terminal
2
synaptic maturation
synaptic maintenance
neurotransmitter homeostasis
ion homeostasis
volume homeostasis
ECM
synaptic extinction (?)
microglial
process
postsynaptic neuron
Figure 1. Astroglial cradle embraces and fosters multi-partite synapse in the CNS. The majority of synapses in the brain and spinal cord are composed of several
components that include: the presynaptic terminal; the postsynaptic part; the perisynaptic process of the astrocyte; the process of a neighbouring microglial cell that
periodically contacts the synaptic structure; and the ECM present in the synaptic cleft and also extending extra-synaptically. Astroglial perisynaptic sheaths enwrap
synaptic structures and regulate, influence and assist synaptogenesis, synaptic maturation, synaptic maintenance and synaptic extinction. (Online version in colour.)
components outlined above [3–8]. In physiology, the concept
of the multi-partite synapse (mainly in its ‘tripartite’ version)
is linked to the idea of fast ‘gliotransmission’, which postulates
that Ca2þ-regulated exocytotic release of neurotransmitters
from astrocytes directly contributes to synaptic transmission.
The gliotransmission has recently been overviewed in detail
[9], although its importance for synaptic physiology remains
a controversy [7,10–13]. Debates on this matter, which
have generated much emotion in the neuroglial field, are
outside the scope of the current narrative, although we are
favouring the notion that fast gliotransmission plays little
role in physiological activity of multi-partite synapse.
Each and everyone of the synaptic structural components
plays a distinct role in the life of the synapse, from its appearance and maturation to its maintenance and, if needed, to its
extinction. The microglia cells appear in the CNS from the
very early embryonic period [14], and, being essentially the
first glial cells existing in the developing CNS, possibly contribute to early synaptogenesis; at the later developmental stages,
microglial cells are fundamental for shaping synaptic connectivity through, for example, synaptic pruning/stripping
[15,16]. Similarly, the ECM regulates synaptogenesis, interconnects pre- and postsynaptic protein complexes, controls
receptor trafficking through integrins-mediated signalling
and modulates postsynaptic excitability [5,17–20]. In this
brief essay, we shall overview the contribution of astroglia to
the life of a synapse in the CNS.
processes (known as PAPs); these latter are identified by immunoreactivity to glutamate synthetase and glutamate transporters
and are devoid of glial fibrillary acidic protein (GFAP) [21,22]. In
total, about 60% of synapses in the CA1 area of the hippocampus
are enwrapped with membranes of protoplasmic astrocytes;
furthermore, this coverage seems to vary between different
synapses: astroglial processes surround approximately 90% of
all large mushroom spines and perforated synapses [23],
whereas only 50% of small macular synapses are enclosed
with astroglia. In the cerebellum, almost all of the synapses
formed by parallel fibres on the dendrites of Purkinje neuron
are tightly covered by terminal processes of Bergmann glial
cells; these glial structures are quite complex, sprouting from
specialized appendages that protrude from the main shaft of
Bergmann glial processes [24]. The perisynaptic astroglial
sheaths covering synapses are exceedingly thin, the profiles of
these perisynaptic structures being on average less than
200 nm (and often less than 100 nm) in diameter [22]. Importantly, astroglial PAPs demonstrate remarkable morphological
plasticity, when through retracting or extending astroglial membranes the degree of synaptic coverage can be dynamically
regulated [25]. It has to be noted, however, that the data on
synaptic coverage by astroglial processes remain generally insufficient with only a few brain regions being investigated; the
detailed cartography of astroglial synaptic profiles throughout
the CNS is very much longed for.
(b) Physiology
2. Astroglial synaptic coverage
(a) Morphology
The majority of synapses in the CNS are covered with perisynaptic astroglial sheaths that emanate from peripheral astroglial
The perisynaptic astroglial membrane represents the major
part of the cell surface area, accounting for approximately
80% of the total astroglial plasmalemma, and yet it contributes
only a minor fraction (approx. 4–10%) to the cellular volume,
this being reflected by an extremely high surface-to-volume
ratio (around 2521 mm [26]). This in essence means that the
Phil. Trans. R. Soc. B 369: 20130595
astroglial
perisynaptic
sheath
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synaptogenesis
synaptic isolation
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potassium
homeostasis
3
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Kir4.1
NKA
KCC1
K+
2K+
1K+
3Na+
1Cl–
K+
EAAT1,2
GAT1,3
1Cl–
1Glu–
3Na+
1H+
GlyT1
GABA
1Cl–
2Na+
GLY
Xc–
SN1,2
1H+
ENT1
1CYS
2Na+
ADO
1K+
1Na+
pH
homeostasis
NHE
calcium
homeostasis
metabolic
support
ROS
homeostasis
NCX
MCT1
NAAT
NBC
1Na+
1Na+
2/3HCO3–
1GLN 1GLN
3Na+
1Ca2+
2Na+
1ASC
lactate
1H+
3Na+
direct
mode
1Ca2+
reverse
mode
Figure 2. Homeostatic molecular cascades localized in astroglial perisynaptic processes. (Online version in colour.)
perisynaptic astroglial membrane sheath is limited to
plasmalemma with very little cytosol. Such a morphological
arrangement provides an excessive space for receptors, channels, transporters and pumps that contribute to dynamic
neuronal–glial signalling and accomplish glial homeostatic
function; at the same time, shifting of all homeostatic molecules
to glial membranes allows maximal density of exocytotic
machinery in the presynapse and neurotransmitter receptors
in the postsynaptic membrane. Astrocytes possess a highly
heterogeneous complement of neurotransmitter receptors
(both iono- and metabotropic), expression of which varies
between brain regions, being most probably regulated by the
local chemical environment [27]. Astroglial ionotropic receptors are activated by neurotransmitters released in the course
of synaptic transmission and create local transient microdomains of high concentration of cytosolic Ca2þ and Naþ
that represent a substrate for glial excitability. The perisynaptic
processes also contain numerous transporters critical for
homeostatic transport of ions, neurotransmitters, glutamine,
lactate, etc. (figure 2). These transporters create substantial
ion fluxes; the PAPs and perisynaptic astroglial compartments
are generally poor in organelles [22], and in particular they are
almost completely devoid of endoplasmic reticulum [28]
making transmembrane ion fluxes fundamental for local ion
signalling mediated by both Ca2þ and Naþ [29,30].
3. Astrocytes cradle: fostering and maintaining
synaptic connectivity
The intimate relationship between perisynaptic astroglial compartments and central synapses is synthesized in a concept of
the astroglial cradle [7], which appears as a fundamental
element in the life of a synapse, being involved in synaptic genesis and maturation and providing lifelong support for the
synaptic function (figure 1).
(a) Synaptogenesis and synaptic maturation
The life of the synapse progresses through several stages
that include (i) formation of an initial contact between the terminal and postsynaptic neuron, (ii) maturation of the synapse,
(iii) its stabilization and maintenance and (iv) elimination.
Phil. Trans. R. Soc. B 369: 20130595
neurotransmitter
homeostasis
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A fundamental function of the astroglial cradle is synaptic isolation, when perisynaptic astroglial sheath shields the synapse
from the outer space, preventing both ‘spill-over’ of the transmitters from the synaptic cleft and ‘spill-in’ of the transmitters into
the cleft from the extra-synaptic structures [7]. This idea of synaptic isolation or insulation has a long history, being invented by
Santiago Ramon y Cajal (who credited his brother Pedro with
the suggestion [39]). The astroglial cradle isolates synapses
both mechanically (by enwrapping synaptic structures with
perisynaptic membranes) and functionally by active neurotransmitter uptake, although of course not all the synapses are fenced
by astroglial membranes and the functional consequences for
these ‘open’ synapses remain to be investigated.
(c) Ion homeostasis
Ion homeostasis of the extracellular space is of paramount
importance for CNS function; fluctuations in extracellular ion
concentrations rapidly affect excitability of neurons that may
cause numerous adverse effects. This is particularly important
for Kþ ions that travel across neuronal membranes firing
action potentials and postsynaptic membranes activated
by neurotransmitters.
(i) Potassium buffering
Astrocytes are central for extracellular Kþ homeostasis in the
CNS, their critical role being recognized by Leif Hertz in 1965
(ii) Proton homeostasis and pH regulation
Astrocytes are indispensable for regulation of pH in the CNS
interstitium by providing transmembrane transport for Hþ (by
sodium–proton exchanger, SLC9A1/NHE-1) and bicarbonate
(through sodium–bicarbonate co-transporter SLC4A4/NBC).
In addition, astrocytes contribute to extracellular Hþ levels
through the lactate transporter SLC16A1/MCT-1, which
co-transports 1 Hþ with 1 lactate, and through glutamate transporters, which remove 1 Hþ from the extracellular space together
with each glutamate molecule (see [47] for details).
(iii) Other ions
Astrocytes contribute to homeostasis of other biologically
relevant ions. In particular, activation of astroglial anion
channels trigger Cl2 efflux (because of high cytosolic Cl2 concentration) that is activated for example in hypo-osmotic
stress. Astrocytes can also accumulate Cl2 by NKCC1. Astrocytes participate in Zn2þ homeostasis [48], being endowed
with ZnTs/SLC30 transporter; incidentally the latter may mediate astroglial Zn2þ release in hypo-osmotic conditions [49].
Finally astrocytes, may, at least in principle, contribute to restoration of extracellular Ca2þ in the cleft after periods of intense
neuronal activity that may substantially decrease [Ca2þ]i [50].
Lowering extracellular Ca2þ can trigger astroglial intracellular
Ca2þ release [51]; and Ca2þ may subsequently leave the
astrocyte through the Naþ/Ca2þ exchanger.
(d) Neurotransmitter homeostasis
(i) Glutamate
Astroglial cells are fundamental elements of glutamatergic
transmission in the CNS that control the extracellular distribution of glutamate and maintain the neuronal glutamate
pool by supplying glutamine. Astrocytes regulate extracellular
glutamate concentration by balancing glutamate uptake
through Naþ-dependent astroglia-specific glutamate transporters (SLC1A3/EAAT1 and SLC1A2/ EAAT2) and glutamate
release mainly through the cysteine–glutamate exchanger or
system Xc2 (SLC7A11) [52,53]. These two types of transporters
are differentially expressed in the astroglial membranes so that
glutamate uptake dominates around the synaptic cleft,
whereas cysteine–glutamate exchangers are concentrated in
extra-synaptic regions. In the synaptic cleft at rest, glutamate
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(b) Synaptic isolation
[40]. The astroglial Kþ removal system is represented by several complementary molecular mechanisms that include
Naþ/Kþ ATPase, inward rectifying Kir4.1 channels, Kþ/Cl2
co-transporter KCC1 (SLC12A4) and Naþ/Kþ/Cl2 cotransporter NKCC1 (SLC12A2) [41,42]. More recent data suggest
that inhibition of Naþ/Kþ ATPase reduced post-stimulus clearance of Kþ transients, whereas inhibition of Kir4.1 channels and
NKCC1 had minor effects [43]. The transporters are regulated
by [Naþ]i and (indirectly) by [Ca2þ]i: for example, increase in
astroglial Ca2þ activates the forward mode of the Naþ/Ca2þ
exchanger that mediates substantial Naþ influx, which in turn
stimulates Naþ/Kþ ATPase and alters the Naþ electro-driving
force that maintains functional activity of relevant SLCs [44]. Potassium buffering not only removes excess Kþ but also affects
short-term plasticity for example in hippocampal synapses
[44,45]. Potassium ions, accumulated by astrocytes, can subsequently dissipate through astroglial syncytium through the
mechanism known as spatial Kþ buffering [46].
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Once formed, synapses survive for several hours in the early
postnatal period and for days and month in the adult CNS
[31]. The major wave of genesis of glutamatergic synapses in
the mammalian brain occurs in the early postnatal period (postnatal weeks 1–3 in rodents); this wave of synaptogenesis
immediately follows massive astrogliogenesis [32]. Astroglia
contribute to synaptogenesis through secreting various factors,
in particular cholesterol [33] and thrombospondins; the latter
are an astroglia-derived component of ECM. Thrombospondins
exert their effects through an accessory subunit of voltage-activated calcium channels identified as a2/d1 protein (or
CaCna2d1) [18]. Astrocytes may also promote synaptogenesis
through oestradiol, g-protocadherins, integrins and protein
kinase C [34]. Not all central synapses require glia, and for
instance inhibitory GABA-ergic contacts develop before the
profuse appearance of astrocytes [35].
Similarly, factors produced and secreted by astrocytes
enhance and facilitate maturation of synapses affecting both
pre- and postsynaptic neuronal compartments. These astrogliaderived molecules include activity-dependent neurotrophic
factor and tumour necrosis factor a which regulate the trafficking of glutamate receptors into postsynaptic membranes,
whereas cholesterol may enhance neurotransmitter release
from presynaptic terminals [36].
Astrocytes may also regulate the number of synapses on
the given neuron by denying presynaptic terminals the contact with postsynaptic membranes and can be involved in
synapse elimination. In particular, astrocytes in vitro have
been found to label synaptic terminals with complement
factor C1q, this tag being recognized by microglia with subsequent selective phagocytotic removal of the synaptic
contact [36,37]. Other mechanisms may also exist, although
the overall role and contribution of astrocytes to synaptic
extinction remains controversial [38].
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Similar to glutamate, inhibitory transmission mediated by
GABA and glycine is terminated through transmitter uptake.
Astrocytes express Naþ-dependent GABA transporters 1 and
3 (SLC6A1/GAT1 and SLC6A11/GAT3); GABA taken up by
astroglia is converted to glutamine or is metabolized by
GABA-transaminase to succinic semialdehyde [52]. Astroglial
GABA transporters can reverse by moderate depolarization
or relatively minor (by 5–7 mM) increase in [Naþ]i, thus turning an astrocyte into a GABA source [60]; GABA can possibly
leave astrocytes also through plasmalemmal channels [61].
Astroglial glutamine is critical for maintenance of GABAergic transmission through the glutamate–glutamine/GABA
shuttle; inhibition of the latter rapidly occludes GABAmediated inhibitory transmission [62]. Astroglia predominantly express glycine transporter GlyT1 (SLC6A9), which, in
contrast to neuronal GluT2 (SLC6A5), can be reversed in
response to physiological fluctuations of membrane potential
and/or [Naþ]i [52].
(iii) Adenosine
Astrocytes are primary regulators of adenosine levels in the
CNS through the astroglial adenosine cycle; adenosine is transported to astroglia via equilibrative ENT1 (SLC29A1)
(e) Water transport and synaptic cleft volume
regulation
Astrocytes provide the main conduit for water movements in
the CNS by the virtue of dense expression of aquaporin
AQP4 (that is the main water channel in the nervous system);
these channels are specifically concentrated in the perivascular
and subpial endfeet and, to a lesser extent, in the perisynaptic
astroglial membranes. The AQP4 channels are co-localized
with Kir4.1 channels, thus coupling water and Kþ movements
[66,67]. While AQP4 displays a highly polarized expression in
astrocytic vascular endfeet, Kir4.1 is more uniformly distributed across the cell body and perisynaptic processes. The
difference in spatial distribution of the two proteins questions
the coupling between water and Kþ movement through
AQP4 and Kir4.1. It has to be noted, however, that recent
observations on AQP42/2 mice found facilitated spatial Kþ
buffering further supporting the role for AQP4 in regulation
of Kþ homeostasis. The water fluxes are relevant for synaptic
transmission, because synaptic activity is linked to a transient
decrease of the volume of extracellular space and the synaptic
cleft, this decrease being chiefly a function of astroglia. The
transient shrinkage of the cleft contributes to an increase of
effective concentration of neurotransmitter and further limits
neurotransmitter spillover. It is postulated that the transient
volume change is triggered by astroglial accumulation of glutamate, Kþ and CO2 (the latter being taken up by Naþ =HCO3 co-transporter SLC4A4/NBC). Accumulation of these molecules increases local osmotic pressure and stimulates AQP4mediated water intake; removal of extracellular water leads to
shrinkage of the synaptic cleft. Water accumulated onto the
astroglial perisynaptic compartment is subsequently redistributed through the glial syncytium and is extruded distantly [68,69].
(f ) Energy support
Neurons do not have direct access to the vasculature and
depend on astrocytes for supply of energy metabolites. The
many glucose transporters, primarily GLUT1, present in the
astrocytic plasma membrane [70] facilitate diffusion of glucose
to energy demanding synapses, which are often located at a
considerable distance from the vasculature. Diffusion in the
interstitial space is a relatively slow process in complex brain
tissue [71]. It is therefore an open question whether simple diffusion is sufficient to ensure that synapses located at a distance
of 20–50 mm from the vasculature [72] receive sufficient supply
of glucose during periods of high neural activity. For example,
in vivo imaging of NADH has shown that oxygen diffusion is
inadequate to supply oxygen to distant tissue, resulting in
the appearance of watershed regions that experience hypoxia
during physiological activity (e.g. in response to whisker
stimulation) [73]. Glucose is more than 10-fold larger than
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(ii) GABA and glycine
transporters and is catabolized intracellularly by adenosine
kinase that in the CNS is expressed exclusively in astrocytes
[63]. Whether astrocytes or neurons represent the main
source for extracellular adenosine (either released directly or
derived from degradation of ATP) remains a matter of debate
[64,65]. Nonetheless, astrocytes are most likely the main sink
for adenosine because adenosine kinase activity keeps cytosolic
adenosine levels low, thus allowing equilibrium transporter
to generate adenosine influx. This is a vital function, and
transgenic deletion of adenosine kinase is lethal [63].
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is kept at low nanomolar levels (that prevents desensitization
of glutamate receptors) and a high density of glutamate transporters ascertains rapid clearance of glutamate upon synaptic
transmission. Extra-synaptically, however, glutamate is maintained at low micromolar concentrations that provide for
tonic modulation of synaptic transmission and plasticity
through extra-synaptic metabotropic (and possibly NMDA)
glutamate receptors [53].
Besides providing for glutamate clearance and controlling interstitial glutamate distribution, astrocytes maintain
glutamatergic transmission through supplying neurons with
glutamate precursor, glutamine. The latter is synthesized
solely by astroglia-specific glutamine synthetase and is fed
to neurons through a coordinated amino acid transporting system. Astrocytes express Naþ/Hþ-dependent sodium-coupled
neutral amino acid transporters SN1/SNAT3/SLC38A3
and SN2/SNAT5/SLC38A5, which mediate glutamine efflux,
whereas neurons specifically express the sodium-coupled
neutral amino acid transporters ATA1/SNAT1/SLC38A1 and
ATA2/SNAT2/SLC38A2, which act as influx transporters
mediating glutamine accumulation into the neuronal compartment [54]. Glutamate uptake, glutamate conversion by
glutamine synthetase and glutamine transport together represent the glutamate–glutamine shuttle that maintains a
releasable pool of neuronal glutamate and sustains glutamatergic transmission [55,56]. Release of glutamine by astrocytes is
linked to synaptic activity; increase in synaptically released
glutamate increases astroglial release of glutamine, this process
possibly being mediated through activation of glutamate transporters and consequent increase in cytosolic Naþ concentration
in perisynaptic astroglial processes [57,58].
Inhibition of this pathway affects glutamatergic transmission differentially in different brain regions: for example,
in the retina neuronal responses disappear in 2 min after inhibition of glutamine synthetase, whereas in hippocampus
glutamatergic activity lasts for some hours after cessation of
glutamine supply [59].
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Macroglial cells of the CNS are organized into complex networks through gap junctions, each formed by several
hundreds of gap junction channels assembled from several
types of connexins, of which Cx30 and Cx43 are predominant
forms (see [77] for comprehensive overview). These networks
or syncytia can be of homo-cellular (astrocytes to astrocytes
and oligodendrocytes to oligodendrocytes) or hetero-cellular
(astrocytes to oligodendrocytes and possibly NG2 cells; this
also known as panglial syncytia) composition; both types of networks were identified in the CNS. Neuroglial syncytia represent
the reticular part of CNS organization being fundamentally
similar to the ‘diffuse neural net’ proposed by Camillo Golgi
[78]. Macroglial networks are anatomically segregated and
have distinct architecture in different brain regions. For example,
in the somatosensory cortex astroglial syncytia are confined to a
single barrel and have little connection to syncytia formed in
neighbouring barrels, whereas in the olfactory bulb coupling
is confined to astrocytes within a single glomerulus [79,80].
Gap junctional connectivity allows intercellular communication
mediated through diffusion of relatively large (up to 1000 Da)
molecules; this type of intercellular signalling may contribute
to an information processing parallel to synaptic networking,
although it awaits investigation.
Macroglial syncytia are important for glial homeostatic
function. The gap junction connected glial networks are central for spatial Kþ buffering (see above), for [Naþ]i waves, for
diffusion of second messengers and hence for long-range
metabotropic signalling of which Ca2þ waves are an example,
for the removal of toxic substances, and for intercellular
trafficking of energy metabolites (e.g. glucose and possibly
ATP) that has been shown to sustain energetic supply for
maintaining synaptic activity [79,81].
The astroglial cradle, with all its highly developed homeostatic pathways, is critical for normal synaptic transmission.
Any disturbances to these molecular cascades that coordinate
fluxes of ions, neurotransmitters, their precursors, amino
acids, water, etc., as well as remodelling of astroglial synaptic
coverage may profoundly affect synaptic strength, alter
synaptic connectivity and thus contribute to neuropathology.
For example, impaired astroglial Kþ buffering is a central
event in numerous brain pathologies from spreading depression and migraine to hepatic encephalopathy [82,83]. Altered
glutamate uptake represents a key pathogenetic step in
toxic encephalopathies (such as Wernicke encephalopathy
in which severe downregulation of astroglial glutamate transporters expression results in massive neuronal death [84]) or
in amyotrophic lateral sclerosis, with remarkable downregulation of EAAT1/2 identified in various animal models of
the disease [85,86]. Alternatively, deregulation of glutamate
homeostasis through downregulation of cystine/glutamate
Xc2 exchange is induced by chronic nicotine or cocaine
abuse, which might be responsible for the development of
addiction [87]. Reduced synaptic coverage, possibly responsible for disrupted synaptic connectivity and synaptic loss, is
documented in neurodegenerative diseases [88,89]. Astroglia
seem to be involved in the pathogenesis of major psychiatric
disorders such as schizophrenia and major depression, which
are characterized by a loss of astrocytes that can impair neurotransmitter balance which in turn is regarded as a main
pathogenetic event in these disorders [90,91].
Accordingly, molecules involved in astroglial homeostasis
represent potential therapeutic targets, and indeed several
drugs capable of enhancing functional activity of astrocytic glutamate transporters are already identified. These, for example,
include beta lactam antibiotics such as ceftriaxone, which
showed neuroprotective potential and positive outcomes in
several animal models of neurodegenerative diseases, stroke,
and addictive and psychiatric disorders [92–95].
5. Conclusion
The concept of the astroglial cradle unifies multiple astroglial
functions that assist in genesis and support of the normal function of synaptic transmission. This is achieved by numerous
molecules expressed in perisynaptic processes of astrocytes
that provide for homeostatic control over the synaptic cleft, catalyse metabolism of neurotransmitters and ascertain synaptic
isolation. These ‘homeostatic’ molecular cascades present in
the astroglial membrane regulate synaptic connectivity and
synaptic plasticity in wide temporal domains and may constitute a fundamental mechanism of astroglial contribution to
information processing and higher brain functions. These molecular cascades are subject to pathological remodelling and
represent a new class of pharmacological targets that may
underlie novel therapeutic strategies for various classes of
neurological diseases.
Funding statement. M.N.’s research is supported by the National Institutes
of Health (NIH). A.V. was supported by the Alzheimer’s Research
Trust (UK), by the European Commission, by IKERBASQUE and by
a research grant of Nizny Novgorod State University.
6
Phil. Trans. R. Soc. B 369: 20130595
(g) Syncytial connectivity and astroglial homeostatic
capabilities
4. Translational outlook: disruption of astroglial
cradle triggers synaptopathy and contributes
to the loss of synaptic connectivity
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oxygen and can only pass through plasma membranes by facilitated transport. It is therefore predicted that glucose diffusion is
much slower than oxygen. We speculate that the convective
fluxes of cerebrospinal fluid (CSF) that enter the brain parenchyma via the para-arterial space support the rapid transport of
glucose within the brain parenchyma. The convective interchange of paravascular fluid with interstitial fluid will literally
flush glucose after it is transported across the blood–brain
barrier into the brain tissue. The result is the facilitated delivery
of glucose to synapses located far from the vasculature by convective flow of interstitial fluid, supported by astrocytic AQP4
channels [74].
Astrocytes have also been implicated in the CNS energy
metabolism through the operation of the ‘astrocyte–neuron
lactate shuttle’ (ANLS) [75] that is supposed to supply neuron,
in an activity-dependent manner, with lactate acting as an
energy substrate. Increase in astroglial [Naþ]i because of operation of glutamate transport activates Naþ/Kþ ATPase and the
latter, through stimulation of phosphoglycerate kinase, triggers
anaerobic lactate production and subsequent channelling of
lactate to neurons though monocarboxylase transporters,
SLC16A3/MCT-4 or SLC16A1/MCT-1 located in glia and
SLC16A7/MCT-2 expressed in neurons. Aerobic glycolysis
occurs in the absence of mitochondria and hence may proceed
in mitochondria-poor PAPs and astroglial perisynaptic sheath,
being thus a source for local energetic support of active synapses.
The concept of ANLS, however, remains disputed [76].
Downloaded from http://rstb.royalsocietypublishing.org/ on June 16, 2017
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Glossary
(Appropriate gene names are given in parentheses)
Glu
glutamate
GABA
g-aminobutyric acid
GLY
glycine
ADO
adenosine
Potassium homeostasis:
NKA
Naþ/Kþ ATPase or ATP-dependent
Naþ/Kþ pump, the a2 subtype
(ATP1A2) is predominantly expressed
in astrocytes
Kir4.1
inward rectifier Kir4.1 channels
KCC
Kþ/Cl2 co-transporter (SLC12A4)
Neurotransmitter homeostasis:
EAAT1,2
excitatory amino acid transporters 1
(SLC1A3) and 2 (SLC1A2)
GAt1,3
GABA transporters 1 (SLC6A1)
and 3 (SLC6A11)
GlyT1
glycine transporter 1 (SLC6A9)
Naþ/Hþ-dependent sodium-coupled
neutral amino acid transporters 1
(SLC38A3) and 2 (SLC38A5)
Xc2
cysteine –glutamate exchanger (SLC7A11)
ENT1
equilibrative adenosine transporter 1
(SLC29A1)
pH homeostasis:
NHE
sodium-proton exchanger 1 (SLC9A1)
NBC
sodium-bicarbonate co-transporter
(SLC4A4)
Metabolic support:
monocarboxylase transporter 1 (SLC16A1)
MCT-1
monocarboxylase transporter 4 (SLC16A3)
MCT-4
monocarboxylase transporter 2 (SLC16A7)
MCT-2
Reactive oxygen species homeostasis:
NAAT
Naþ-dependent ascorbic acid
transporter (SLC23)
SN1,2
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