The homeostatic astroglia emerges from
evolutionary specialization of neural cells
rstb.royalsocietypublishing.org
Review
Cite this article: Verkhratsky A, Nedergaard
M. 2016 The homeostatic astroglia emerges
from evolutionary specialization of neural cells.
Phil. Trans. R. Soc. B 371: 20150428.
http://dx.doi.org/10.1098/rstb.2015.0428
Accepted: 15 March 2016
One contribution of 15 to a Theo Murphy
meeting issue ‘Evolution brings Ca2þ and
ATP together to control life and death’.
Subject Areas:
neuroscience, evolution
Keywords:
astroglia, evolution, astroglial cradle,
multipartite synapse, memory, neuropathology
Authors for correspondence:
Alexei Verkhratsky
e-mail: alexej.verkhratsky@manchester.ac.uk
Maiken Nedergaard
e-mail: nedergaard@urmc.rochester.edu,
nedergaard@sund.ku.dk
Alexei Verkhratsky1,2,3,4 and Maiken Nedergaard5,6
1
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
2
Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
3
Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain
4
5
University of Nizhny Novgorod, Nizhny, Novgorod 603022, Russia
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
6
Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of
Copenhagen, Copenhagen 2200, Denmark
Evolution of the nervous system progressed through cellular diversification
and specialization of functions. Conceptually, the nervous system is
composed from electrically excitable neuronal networks connected with
chemical synapses and non-excitable glial cells that provide for homeostasis
and defence. Astrocytes are integrated into neural networks through multi-
partite synapses; astroglial perisynaptic processes closely enwrap synaptic
contacts and control homeostasis of the synaptic cleft, supply neurons with
glutamate and GABA obligatory precursor glutamine and contribute to
synaptic plasticity, learning and memory. In neuropathology, astrocytes
may undergo reactive remodelling or degeneration; to a large extent, astroglial
reactions define progression of the pathology and neurological outcome.
This article is part of the themed issue ‘Evolution brings Ca2þ and ATP
together to control life and death’.
1. Evolution of the nervous system: cellular distribution of
functions
The human brain, which crowns 3.5 billion years of biological evolution, is argu-
ably the most complex structure known to the natural sciences. The brain tissue is
composed out of approximately 200 billion neurons and neuroglial cells that are
connected by more than 15 trillion electrical and chemical synapses into the net-
works with extraordinary computing and memory storage capacity—the latter
being estimated to reach a petabite mark [1]. High density of electrically excited
cells, which rely on constant movement of ions across their membranes, the pro-
cess requiring ATP in quantity (a single human cortical neuron is claimed to use
approximately 4.7 billion ATP molecules per second [2]), makes the brain the
major energy consumer in the organism [3]. The high disbursement of ATP stipu-
lates high mitochondrial activity, whereas the oxidative phosphorylation
produces reactive oxygen species that have to be scavenged to avoid profound
cellular damage. Ion redistribution associated with brain activity has to be con-
trolled, as ion accumulation in the extracellular space seriously affects neuronal
excitability. Similarly, the neurotransmitters released in the course of synaptic
transmission have to be properly handled to exclude associated neurotoxicity
(and glutamate, the main excitatory neurotransmitter, is the most effective
endogenous neurotoxin). Finally, these cellular networks and the cells making
them are constantly changing their structure, which underlies neural plasticity
and learning. These are only a few of the major logistical problems associated
with brain function, which are managed surprisingly well in the course of
about 100 years of human life. Even more remarkably, the human brain is
highly resilient to the passing years and the brain appears as one of the most
age-resilient systems of the human body. Indeed, the 40-year-old athlete
cannot compete in the sprint with youngsters, whereas a 60-year-old academic
has, as a rule, much higher intellectual output than many of his 20-year-old
& 2016 The Author(s) Published by the Royal Society. All rights reserved.
students. This reflects a remarkable plasticity of the human
brain, which is optimized for learning thus recompensing
the age-dependent alterations.
The maintenance of the brain tissue throughout life is the
function of specialized cells classified as neuroglia. The neu-
roglial cells are represented by astroglia, oligodendroglia and
NG2 glia all of neuroepithelial (i.e. ectodermal) origin, and
microglial cells that derive from foetal microphages (of meso-
dermal descent) that enter the nervous system very early in
embryogenesis [4– 6]. In the human brain, the total number
of glial cells is more or less similar to that of neurons,
although with prominent regional differences [7,8]. Evolutio-
narily, emergence of neuroglia coincided with the appearance
of the centralized nervous system; there is little sign of
supportive cells in the diffuse nervous system [9]. The
proto-astrocytes are well-defined in round worms, where
they contribute to the development and maintenance of the
nervous system (especially its the sensory arm; the glial cells
form sensory organs of the worm, known as sensillas),
although artificial ablation of this primeval glia does not
exterminate the animal [10,11]. In more advanced invertebrates,
glia diversifies; ganglia in leeches and ‘brains’ of insects con-
tain many types of ‘homeostatic’ glia analogous to astrocytes,
whereas axons in some types of molluscs and arthropods are
covered by multiple lamellae of covering glia analogous to
Schwann cells and oligodendrocytes [12 –15]. The nervous
tissue macrophages or primeval microglial cells are known
to populate the ganglia of leeches and bivalves [16]. Concep-
tually, therefore, from the very beginning of evolutionary
development of central nervous system, the cellular division
of functions emerged: the neurons become mostly respon-
sible for rapid propagation of signals associated with action
potentials and chemical synapses, whereas neuroglia
assumed the responsibility for homeostasis and defence.
This specialization occurred in evolution at least twice,
because the appearance of chordates and vertebrates
coincided with fundamental change in neuroglia. This funda-
mental change is manifested by an emergence of a new type
of glial cell, the radial glia [17], which signalled the new
organization of the CNS in layers in contrast to fused ganglia
of invertebrates. The radial glia emerged in the Echinoder-
mata (e.g. sea urchin, star fishes, sea cucumber), the early
relatives of Chordata. Neuroglia in these species are rep-
resented, almost entirely, by the radial glia with elongated
shape, long processes, perpendicular orientation to the sur-
face of the neuroepithelium and high level of expression of
intermediate filaments glial fibrillary acidic protein (GFAP)
and vimentin [18]. Similarly, the radial glia are the main
type of parenchymal glia in early vertebrates including elas-
mobranchii (sharks and rays) and teleosts (for example, zebra
fish). The radial glia dominate the so-called laminar-type
brains, with thin parenchyma and neurons mainly concen-
trated in the periventricular zone. In the larger and thicker
brains with clear layered organization, the true parenchymal
(i.e. protoplasmic) astrocytes are identified [19,20]. In the
zebra fish (which also possesses a relatively thin brain), the
radial glia is the only type of astroglia-like cells; processes
of these cells extend through the entire width of the brain
from the ependymal coating of the ventricles to the pial sur-
face; zebra fish radial glial cells express GFAP, glutamine
synthetase and aquaporin-4 and they seemingly perform all
homeostatic functions congenital to astroglia. The reaction
of zebra fish glia to injury is however idiosyncratic: instead
of mounting a reactive response, the radial glia increase pro- 2
liferation and neurogenesis; as a result, zebra fish never
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produce scars in their brain, but counteract the lesion by
substituting damaged cells [21]. An increase in the thickness
of the brain is associated with an appearance of specialized
parenchymal astrocytes; the very same scenario [22] operates
in developing mammalian brains when radial glia populating
the neural tube are eventually substituted by various types of
parenchymal astrocytes (although some neuroglia with radial
properties remain in certain areas; for example, Bergmann
glial cells in cerebellum, Müller glia in the retina or tanycytes
in the hypothalamus [17]).
Phil. Trans. R. Soc. B 371: 20150428
2. Astroglial integration into neural networks:
the multipartite synapse
The neural tissue of the CNS is organized in a form of highly
complex cellular networks composed of neural cells (neurons,
astrocytes, NG2 cells and oligodendrocytes), microglia of
mesodermal origin and blood vessels, formed by muscle
and endothelial cells and containing various types of
blood cells. All these elements form multiple connections
that allow a high degree of coordination. In these settings,
astroglia assume control over extracellular homeostasis of
neurotransmitters, ions, reactive oxygen species; astrocytes
are responsible for local metabolic support, for regulation of
extracellular volume, for regulation and maintenance of
synaptic connectivity, for secretion of numerous trophic and
humoral factors and many more [7,23– 29]. Astrocytes are
important elements of brain cytoarchitecture; they provide
for tiling in the grey matter hence creating astroglio-neuro-
vascular units that integrate neuronal and vascular
elements residing within the territorial domain of an individ-
ual protoplasmic astrocyte [30,31]. Astrocytes display a
remarkable heterogeneity between brain regions; astroglia
differ in morphological appearance, in expression of ion
channels, receptors and transporters and in their functional
specialization [7,32 –37]. Differential expression of neuro-
transmitter receptors in astrocytes from different regions of
the brain exemplifies their functional heterogeneity. Astro-
cytes, potentially, can express all neurotransmitter receptors
existing in the brain, which was demonstrated in early exper-
iments performed in vitro in primary cell cultures [38]. In the
nervous tissue in situ, however, glial expression of neuro-
transmitter receptors differs substantially between brain
regions, the specific repertoire of receptors being, most
likely, controlled by the local neurochemical environment.
Indeed, the complement of receptors borne by astrocytes in
a given brain area is, as a rule, congruent to the main
neurotransmitters released in this particular part of the
CNS [39]. For example, glycine receptors are expressed in
astrocytes in the spinal cord (where glycine acts as a
main inhibitory neurotransmitter), dopamine receptors are
present in astroglial cells in substantia nigra (where dopamin-
ergic transmission dominates), whereas Bergmann glia in
cerebellum express adrenoceptors, purinoceptors, histamine,
GABA and glutamate receptors, all reflecting neuro-
transmitters released in their vicinity [40–45]. Physiological
properties of astrocytes can be further sculpted by
signalling influences from neighbouring neurons; these
influences in particular may be mediated by Sonic Hedgehog
morphogenes [46].
 Activation of glial receptors conveys chemical trans-
mission from neurons to astrocytes, and initiates a specific
form of astroglial excitability mediated by spatio-temporal
cytosolic changes in the concentration of several ions, most
notably Ca2þ, Naþ and Kþ. Astroglial calcium signalling
[45,47,48] can be global (mainly owing to Ca2þ release from
the endoplasmic reticulum Ca2þ store) or local (mainly
mediated by Ca2þ entry through plasmalemmal channels
and Naþ/Ca2þ exchanger); these Ca2þ signals regulate cellu-
lar metabolism and gene expression, as well as trafficking
and release of secretory vesicles. Dynamic changes in cytoso-
lic Naþ concentration, which occur in response to neuronal
activity, specifically regulate numerous homeostatic molecu-
lar cascades expressed in astrocytes [49 –51]. Increases in
intracellular Naþ in astrocytes originate from Naþ influx
through ionotropic receptors (such as AMPA/NMDA gluta-
mate receptors or P2X purinoceptors [52,53], which all
conduct Naþ currents), by Naþ/Ca2þ exchanger and most
notably by Naþ-dependent glutamate transporter. The transi-
ent receptor potential ‘canonical’ (TRPC) channels expressed
in astroglia provide a link between Ca2þ release from the
endoplasmic reticulum and Naþ influx: TRPC channels are
activated by store-operated mechanism and generate both
Naþ and Ca2þ currents [54]. The transmembrane Naþ gradi-
ent in its turn controls many solute carrier transporters
expressed in astroglial membrane that are responsible for
removal of neurotransmitters (aforementioned glutamate
transporters, GABA transporters, glycine transporters, con-
centrating adenosine transporters), for release of glutamine
(which is the obligatory precursor for neuronal glutamate
and GABA), for accumulation of ascorbic acid, for transport
of protons and bicarbonate, and many more. Besides, astro-
glial Naþ regulates sodium–potassium pump and inward
rectifying Kþ channels (which are the main components of
the Kþ buffering system), glutamine synthetase and mito-
chondrial Ca2þ transport. All in all, [Naþ]i transients are an
important part of glial ion excitability that coordinates
neuronal activity with glial homeostatic responses.
As has been briefly alluded to before, the evolution of the
nervous system progressed through division of function and
cellular specialization. The chemical synapse, which is the
central element of neural connectivity, similarly evolved
through functional specialization of its cellular compart-
ments. In the CNS, most of the synapses are composed
from several elements and hence are known as multipartite
synapses [55 –57]. The main components of multipartite
synapses of the CNS are (i) the presynaptic terminal, (ii) the
postsynaptic part that is often represented 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, which is present in the synaptic cleft and also extends
extrasynaptically. The neuronal part of a synapse is fully
specialized for chemical transmission: the presynaptic term-
inal contains a rather substantial pool of synaptic vesicles
and proteins responsible for multiple stages of exocytotic
release. The postsynaptic membrane contains neurotransmit-
ter receptors; in addition, the postsynaptic neuronal
compartment is densely packed with numerous proteins
responsible for synaptic plasticity [58]. The microglial process
(which is now believed to be a fully legitimate part of a cen-
tral synapse) regularly surveys the synapse and when
necessary prunes it [59,60]; the extracellular matrix regulates
various aspects of receptor trafficking in pre- and postsyn- 3
aptic parts, regulates synaptogenesis, modulates membrane
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excitability and provides a platform for integrin signalling
[61]. The perisynaptic process of an astrocyte, which inti-
mately covers both pre- and postsynaptic parts (the degree
of coverage varies across the CNS; on average, 60 –70% of
central synapses are enwrapped by astroglial membranes),
contains most of the molecules responsible for homeostatic
control of the synaptic cleft and of the synapse at large. The
generic functions of the astroglial compartment are many;
they include regulation and promotion of synaptogenesis
[62], synaptic maturation [24], synaptic maintenance and
Phil. Trans. R. Soc. B 371: 20150428
synaptic extinction [63], and thus the perisynaptic astroglial
comportment can be considered as a synaptic cradle [57,64]
that fosters, sustains and eliminates synapses in the course
of life, thus shaping the neural connectome.
The perisynaptic astroglial processes originate from per-
ipheral astroglial processes of parenchymal astrocytes
(which could be protoplasmic astrocytes in the cerebrum
or Bergmann glial cells in the cerebellum [65,66]). The
perisynaptic process is quite a peculiar structure, with an
extremely high surface-to-volume ratio; the perisynaptic
process is exceedingly thin (approx. 100 nm or even less) and
is almost completely devoid of organelles [67,68], although it
may contain very small (0.2–0.4 mm) spherical mitochondria
[69]. The perisynaptic processes specifically express ezrin and
radixin (which can be used a immunocytochemical markers
[70]); these two are known to associate with actin and hence
contribute to filopodial movements and may therefore partici-
pate in morphological plasticity of astroglial processes [70,71].
Rapid filopodial movements of astroglial processes have
indeed been detected in vitro and in situ [70,72], and it is con-
ceivable that morphological remodelling of perisynaptic
astroglial processes can be an important component of synap-
tic plasticity [73]. Astroglial perisynaptic processes control
homeostasis of the synaptic cleft [57]; for this purpose, they
express numerous transporters, channels and enzymatic
cascades, some functions of which are discussed below.
3. Singular human astrocytes
Evolution of the brain proceeded with steady increase in the
organ’s size, quite obviously reflecting an increase in the
number of neural cells. The total number of neural cells in
low vertebrates is around hundreds, in insects the brain con-
tains approximately 100 000 cells, whereas in humans
approximately 200 billion. The relative number of glial cells
generally increases when progressing through the phylo-
genetic tree. A single ganglia in the leech Hirudo medicinalis
is composed of approximately 400 neurons and only 10–12
neuroglial cells (giving a glia-to-neuron ratio of 0.025),
whereas in mammals, this parameter varies between 0.3 in
rodents and approximately four to eight in elephants and
whales (figure 1). There are, as usual, exceptions: for
instance, the buccal ganglia of the great ramshorn snail
Planorbis corneus has 391 glial cells and 298 neurons, giving
a glial-to-neuron ratio of approximately 1.3 [75]. Precise
numbers of cells in the brain of humans and counts of differ-
ent types of neuroglia are yet to be obtained and verified. All
in all, it seems that the grand totals for neurons and
non-neuronal cells are quite similar: likely the human brain
contains more than 100 billion neurons and in excess of
 (a) (b) 4
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7
rat
6
glia-to-neuron ratio

human
5 20

4
3 10
2
1

Phil. Trans. R. Soc. B 371: 20150428

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Figure 1. Phylogenetical advance of neuroglia. (a) Glia-to-neuron ratio in the nervous system of invertebrates and in the cortex of vertebrates. Glia-to-neuron ratio is
generally increased in phylogenies; more or less, this ratio linearly follows an increase in the size of the brain. (b) Relative increase in glial dimensions and
complexity during evolution. Linear dimensions of human astrocytes when compared with mice are approximately 2.75 times larger and their volume is 27
times larger; human astrocytes have approximately 10 times more processes and every astrocyte in human cortex enwraps approximately 20 times more
synapses. (c) Comparison of morphological appearance (at the same magnification) of mouse, monkey and human protoplasmic astrocytes. Scale bar, 10 mm.
(a,b) Reproduced with permission from [7] and (c) from [74]. (Online version in colour.)

100 billion glial cells (for counts and techniques used, see for
example [7,76–80]). What are the numerical fractions for
different types of glia similarly remains unknown; probably,
it is safe to suggest that human brain contains approximately
10% of microglia, 10% of NG2 cells and the remaining 80%
are shared between oligodendrocytes and astrocytes in yet
undefined proportions. Numerical distribution of neurons
and neuroglia varies between brain regions, and varies
rather substantially: the cerebellum for example contains
the largest number of neurons (ca 70 billion [81]) and
comparatively few neuroglia (about 4–10 billion, giving
glia-to-neuron ratio of approx. 0.1). The relatively low num-
bers of cerebellar astrocytes are compensated by their specific
morphology—the velate astrocytes of cerebellum extend
lamellar-like processes that surround most of granule neur-
ons and possibly even partition glomeruli into independent
units [82,83]. In the cerebral cortex, the ratio between astro-
cytes and neurons is approximately 1.65 [84], whereas in
the brainstem, glial cells may outnumber neurons by a
factor of 10 [8]. In the white matter (that comprises
more than 50% of the total brain volume), neuronal somata
are absent and hence the glia-to-neuron ratio is (formally)
infinite.
Astroglial evolution led to substantial changes in their
appearances, which is particularly evident in the brains of
higher primates and humans. First, classical protoplasmic
and fibrous astrocytes in the human brain are substantially
larger and exceedingly more complex when compared with
rodents or even monkeys (figure 1b,c; [37,74,85]). The average
size of the territorial domain of a human protoplasmic astro-
cyte is approximately 2.5 times larger that formed by a rat
astrocyte (142 versus 56 mm), whereas the volume of the
human protoplasmic astrocyte domain is approximately
16.5 times larger than the volume of the domain associated
with rat astrocyte. Human protoplasmic astrocytes have
approximately 10 times more primary processes emanating
from their somata, and correspondingly much more complex
arborization of terminal processes. As a result, a single
human protoplasmic astrocyte envelops approximately
two million synapses residing in its territorial
domain, whereas rodent astrocytes cover approximately
20 000– 100 000 synaptic contacts [30,85]. Similarly, human
 (a) cortical 5
(b)
layers

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interlaminar I
astrocyte

interlaminar
astrocyte
II
protoplasmic
astrocyte

Phil. Trans. R. Soc. B 371: 20150428

III

IV
(c) varicose
projection
astrocytes

V
varicose
projection
astrocytes
VI

polarized
astrocyte
fibrous
(d) (e) astrocyte

white
matter

protoplasmic fibrous
astrocyte astrocyte
Figure 2. Morphological heterogeneity and subtypes of astrocytes in human cortex. (a) Pial surface and layers 1 – 2 of human cortex. GFAP staining in white; 40 ,6-
diamidino-2-phenylindole (DAPI), in blue. Scale bar, 100 mm. Yellow dashed line indicates border between layers 1 and 2. (b) Interlaminar astrocyte processes. Scale
bar, 10 mm. (c) Varicose projection astrocytes reside in layers 5– 6 and extend long processes characterized by evenly spaced varicosities. Inset: varicose projection
astrocyte from chimpanzee cortex. Yellow arrowheads indicate varicose projections. Scale bar, 50 mm. (d ) Typical human protoplasmic astrocyte. Scale bar, 20 mm.
(e) Human fibrous astrocytes in white matter. Scale bar, 10 mm. (Reproduced with permission from [37]).

fibrous astrocytes are approximately 2.2 times larger than
their rat namesakes [85].
In the higher primates and in humans, several specific
types of astroglial cells, which are absent in all other species,
have been detected. First, these are interlaminar astrocytes;
small (approx. 10 mm) somata of these cells are located in
the cortical layer I, whereas their exceptionally long (approx.
1 mm) processes extend to cortical layers III–V; these pro-
cesses run parallel to each other, forming the so-called
palisade (figure 2b; [86–88]). The second type of human astro-
cytes is represented by polarized astrocytes; these are uni- or
bipolar cells whose somata are placed close to the white
matter in layers V and VI. These cells send one or two very
long processes that end in the neuropil [85]. Finally, the
brain of humans (only) contains varicose projection astrocytes
that have up to five long (up to 1 mm) unbranched processes
that extend in all directions from somata located in the deep
cortical layers. The processes of these cells have evenly
spaced varicosities (figure 2; [85]). The role of all these
human-specific astroglia remains unknown.
Do these larger and extraordinarily more complex human
astrocytes contribute to the computing power of human
brain? This question was directly addressed when
human glial progenitors were injected into the ventricles of
newborn mice [89]. These progenitors differentiated into
mature protoplasmic and fibrous astrocytes as well as into
oligodendrocytes. The human astrocytes maintained their
complex structure in the mouse brain; they also were substan-
tially larger then host astrocytes [89]. Quite unexpectedly, the
human glia bestow a growth advantage to the mouse brain,
whereas human astrocytes populate large parts of both grey
and white matter [90]. When ‘humanized’ (i.e. carrying
human glia) chimeric mice reach adulthood they became
smarter than their littermates that did not receive human
glia progenitor grafts. The humanized mice outwitted their
naive relatives on multiple cognition tests, including novel
object recognition and fear conditioning [89]. At a cellular
level, the presence of human astrocytes leads to a reduction
in long-term potentiation threshold measured in hippocam-
pal slices. Overall, this analysis provides direct evidence
that human astrocytes boost the cognitive abilities of mice,
possibly by increasing neural plasticity.
4. Astroglial homeostatic cascades
(a) Neurotransmitter homeostasis
Neuronal networks communicate using chemical transmit-
ters, which have to be constantly replenished. Turnover and
homeostasis of the major neurotransmitters in the CNS
(glutamate, GABA and adenosine) constitute one of the
most fundamental functions of astroglia. Glutamatergic and
GABAergic transmission require astroglia for maintenance
through continuous supply of glutamine (glutamate –
glutamine– GABA shuttle). Glutamine is synthesized in
astrocytes either through the tricarboxylic acid cycle [91,92]
or directly from glutamate by glutamine synthetase. Gluta-
mine synthetase is a specific astroglial enzyme discovered
by Michael Norenberg and Antonio Martinez-Hernandez
[93,94]. Glutamate is accumulated into astrocytes by two
types of astroglia-specific transporters, the excitatory amino
acid transporters 1 and 2 (EAAT1, EAAT2). Importantly,
both EAAT1/2 and glutamine synthetase are specifically con-
centrated in the perisynaptic astroglial processes surrounding
identified glutamatergic synapses [68,95]. Glutamine pro-
duced in astrocytes is transported back to neurons by using
a coordinated system of neutral amino acid transporters:
astrocytes express Naþ-coupled neutral amino acid transpor-
ters SN1/SNAT3/SLC38A3 and SN2/SNAT5/SLC38A5 that
provide for glutamine efflux (so-called system N); neurons
have distinct complement (the system A) of ATA1/SNAT1/
SLC38A1 and ATA2/SNAT2/SLC38A2 amino acid transpor-
ters, which are specialized for glutamine influx [96].
Astroglial transporters are electroneutral (Naþ influx is
balanced by equivalent efflux of Hþ), whereas the neuronal
system is electrogenic (glutamine molecule is co-transported
with Naþ). As a result, glutamine influx is accompanied
with depolarization and may, in principle, trigger neuronal
excitation [97]. Astroglial secretion of glutamine is directly
coupled with neuronal activity: increase in the latter (and
hence increase in glutamine transport into astrocyte) stimu-
lates release of glutamine by astrocytes [98,99]. Inhibition of
the glutamate–glutamine–GABA shuttle suppresses glutama-
tergic as well as GABAergic transmission in the CNS [100,101].
Astrocytes also contribute to GABA transmission through
expression of Naþ-dependent GABA transporters GAT1/
SLC6A1 and GAT3/GAT3. These transporters are involved
in the removal of GABA from the synaptic cleft. The reversal
potential of astroglial GABA transporters is quite close to the
resting potential (approx. 270 or even 280 mV); therefore,
rather moderate increases in cytosolic Naþ concentration
reverse the transporter, thus leading to GABA release from
astroglial compartment [102]. Astrocytes also express Naþ-
dependent glycine transporters of GluT1/SLC6A9 type,
which also can be reversed upon an increase in cytosolic
Naþ concentration [103]. Finally, astrocytes are critical
elements of the purinergic transmission because they catabo-
lize adenosine that occurs in the CNS following ATP
hydrolysis. Astrocytes accumulate adenosine by equilibrating
(ENT1/SLC29A1) or Naþ-dependent concentrative (CNT2/
SLC28A2) transporters [104]. Accumulated adenosine is sub-
sequently catabolized by adenosine kinase, which, in the
CNS, is preferentially expressed in astrocytes [26].
(b) Astroglia control ion homeostasis 6
Tight control over extracellular ion concentrations is of critical
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importance for CNS functions, as even minor changes may
have far-reaching consequences. At the same time, fluctu-
ations in extracellular ion concentration may represent a
physiologically relevant mechanism for regulation of overall
excitability of neurons and regulate functional status of the
brain. Astrocytes actively control extracellular cations (Kþ,
Naþ and Ca2þ) as well as extracellular protons. Astroglial
Kþ buffering system (discovered by Leif Herz in 1965 [105])
reflects concerted operation of Naþ/Kþ ATPase, inward rec-
Phil. Trans. R. Soc. B 371: 20150428
tifying Kir4.1 channels, and possibly some other
transporters such as the Kþ/Cl2 co-transporter KCC1/
SLC12A4 [106,107]. All these systems mediate local trans-
membrane Kþ transport; local increases in Kþ inside
astrocytes are rapidly equilibrated through astroglial syncytia
by diffusion through connexins/gap junctional channels
(the spatial Kþ buffering [108]). Astrocytes are important
regulators of pH in the brain interstitial space, being
endowed with Naþ/Hþ exchanger NHE-1/SLC9A1,
Naþ =HCO 3 co-transporter NBC/SLC4A4, the lactate trans-
porter MCT-1/SLC16A1, which expels 1Hþ together with
each lactate molecule, and glutamate transporters EAAT1/2,
which remove a single proton from the extracellular space
with each molecule of glutamate [109]. Astrocytes may also
supply extracellular milieu with Ca2þ ions (which can be
depleted upon strong neuronal activity)—decrease in extra-
cellular Ca2þ triggers Ca2þ release from astroglial internal
stores and this Ca2þ can subsequently be extruded through
the Naþ/Ca2þ exchanger [110]. Astrocytes also participate in
regulation of Cl2 (providing Cl2 efflux through anion
channels) and Zn2þ [111].
Consequences of astroglial ion regulation can be signifi-
cant, although the role of physiological fluctuations in ion
composition of interstitial fluid (ISF) remains somewhat
underappreciated. Recent findings of rapid and significant
fluctuations of extracellular Kþ Ca2þ, Mg2þ and Hþ associ-
ated with the sleep/wake cycle highlight the importance of
ion regulation in the CNS [112]. These fluctuations in ion con-
centrations are likely to represent a robust physiological
mechanism that controls global excitability of the CNS and
thus defines the functional status of the brain.
5. Astrocytes and global homeostasis of the
brain: the glymphatic system
Astrocytes are key cellular contributors to the brain-wide
perivascular pathway that supports the exchange of cere-
brospinal fluid and ISF through the recently discovered
glymphatic system [113,114]. The perivascular drainage
system is composed from the vascular muscle cells, endo-
thelial cells, pericytes and astroglial perivascular endfeet.
These latter plaster the vascular wall with approximately
98% coverage [115]; the endfeet are separated by narrow
(approx. 50 nm) clefts that allow certain exchange between
perivascular space and brain parenchyma. The interchange
of ISF and CSF between perivascular space and brain tissue
is driven by pressure gradients arising from arterial pulsati-
lity or vasomotion or respiration; importantly, the CSF
transport into brain parenchyma critically depends on aqua-
porin water channels densely expressed in astroglial endfeet
(see [116] for detailed overview). This continuous interchange
of fluids underlies the clearance of numerous solute mol-
ecules providing for brain cleansing. The glymphatic system
is possibly connected to the sinus-associated lymphatic
vessels, thus creating a global brain lymphatic drainage com-
plex [117]. The status of the glymphatic system is very much
affected by sleep/wake cycle; the activity of glymphatic
clearance markedly increases during the sleep period [118].
The glymphatic clearance severely decreases with ageing
[119], which may be responsible for increased vulnerability
of the aged brain to neurodegeneration, this latter being
associated with accumulation of various pathological
proteins. Very recently, the glymphatic system has been
demonstrated in the human brain [120,121].
6. Astroglial plasticity and memory
Current neuroscience philosophy regards learning and
memory through the prism of synaptic plasticity, when struc-
tural changes, occurring at the synaptic level, outlast memory
stabilization. This concept, proposed by Santiago Ramon y
Cajal more than a century ago [122], implies numerous mol-
ecular changes that occur in all parts of the synapse, leading
to a remodelling of the neural networks that impact onto be-
haviour [123]. Astrocytes, being in intimate contact with
synaptic structures, are likely to contribute to various aspects
of memory formation, storage and retention [124].
Astroglial processes that surround synapses not only pro-
vide for tight homeostatic control over synaptic cleft and
supply neurons with various substances, but they also seem
to stabilize the synapse and prevent it remodelling. In the
process of learning, astroglial processes undergo rapid and
profound changes; for example, in the lateral amygdala, the
implicit memory consolidation of Pavlovian threat condition-
ing is accompanied with retraction of astroglial processes
from the existing synapses. This retraction apparently
allows the enlargement of synaptic contacts [125]. From the
temporal perspective, astroglial processes undergo morpho-
logical metamorphosis in a matter of minutes, hence
allowing rapid synaptic remodelling with subsequent stabil-
ization. Simultaneously, retraction or extension of astroglial
processes affects neurochemical environment by allowing or
denying neurotransmitter spillover [126,127], which might
be another mechanism contributing to memory formation.
Astroglia may also be important for energy support of synap-
tic remodelling during memory formation, which has been
shown to depend rather critically on glycogenolysis that
occurs specifically in astrocytes [128,129]. Similarly, there is
evidence linking long-term memory formation with astro-
glia-dependent supply of neurons with the energy
substrate, lactate [130]. It is of importance that astroglial
energy metabolism is regulated mainly through adrenergic
input; and noradrenalin, in the adult brain, is the main neu-
rotransmitter triggering Ca2þ excitability of astrocytes [131].
It is therefore conceivable that astrocytic Ca2þ signalling
regulates their energy metabolism, including ATP production
and glycogen degradation. At the same time, noradrenalin
controls many aspects of astroglial morphological plasticity.
It is well recognized, from early in vitro studies, that
stimulation of adrenergic receptors or increase in their down-
stream second messenger cAMP induces rapid stellation of
cultured astrocytes [132 –135]. Hence, noradrenergic
innervation can integrate various aspects of astroglial 7
plasticity in the memory-related plasticity.
rstb.royalsocietypublishing.org
7. Neuropathology as a homeostatic failure:
central role for astroglia
From the broad perspective, neuroglia are homeostatic and
defensive cells in the CNS; any type of insult to the nervous
tissue initiates active glial response, whereas neurons are left
to be stressed, to die or to recover. The neurological diseases
can, conceptually, be regarded as homeostatic failure, and
Phil. Trans. R. Soc. B 371: 20150428
hence neuroglial performances, reactions and deficiencies are
central elements that shape neuropathological evolution and
define neurological outcome. This glia-centric view on neuro-
pathology started to develop very recently, and yet it seems
now obvious that a glial component can be distinguished in
every form of neurological disease [136– 142], although under-
standing the precise role of glia and potential of glia as a target
for cell-specific therapies requires tenacious research.
Astroglial contribution to neuropathology is multifa-
ceted, and astrocytes are known to undergo heterogeneous
pathological remodelling, which is directly linked to the
disease context. In many pathological conditions, astroglial
cells undergo degeneration, atrophy and loss of function;
these changes are particularly characteristic for psychiatric
diseases such as major depression and schizophrenia, in
which decrease in astroglial densities is the leading histo-
pathological manifestation [143–146]. Astrodegenerative
morphological changes in neuropsychiatric diseases coincide
with functional abnormalities such as decreased glutamate
and GABA uptake [147,148], or increased production of
kinurenic acid incidentally associated with higher risk of
schizophrenia [149,150]. Moreover, ablation of astrocytes in
the prefrontal cortex (by injection of specific toxin L-a-
aminoadipic acid) was sufficient to induce depression-like
symptoms in adult rats [143]. The leading mechanism of
Wernicke encephalopathy (clinically expressed as Korsakoff
syndrome) is directly associated with profound downregula-
tion of astroglial glutamate transporters with ensuing
excitotoxic neuronal death [151,152]. Astrocytes therefore
are increasingly considered as a legitimate target for cell-
specific therapy in various neuropsychiatric conditions
[153,154].
Another important element of astrogliopathology is rep-
resented by pathological remodelling when astrocytes
acquire abnormal phenotype that contributes to the develop-
ment of neurological disease. Examples of such pathological
remodelling could be found in Alexander disease, where
expression of sporadically mutant GFAP affects astroglial bio-
chemistry that impacts on the developing brain and results in
massive leukomalacia [155]; in hepatic encephalopathy,
where astrocytes undergo profound remodelling of their
homeostatic functions [156]; and in epilepsy, where astrocytes
change their characteristic appearance, lose gap-junctional
coupling and ability to buffer extracellular Kþ, which
together precipitate development of seizures [157].
In neurodegenerative pathologies, both astrodegeneration
and astroglial reactivity appear at different stages of the disease
or may coexist [142]. In amyotrophic lateral sclerosis, for
example, early degeneration and death of astroglia result
in increased excitotoxicity. Astroglia-specific expression of
amyotrophic lateral sclerosis (ALS)-associated hSOD1 mutant
gene, or grafting of hSOD1 mutant-expressing astrocyte precur- integrated into neural networks through multipartite 8
sors into the spinal cord of rodents mimicked symptoms of the synapses, and their remarkable morphological and functional

disease [158,159]. Inversely, silencing of astroglial hSOD-1
delayed and lessened the symptomatology [160]. In Alzhei-
mer’s disease, both astrodegeneration and astroglial reactivity
are observed. Reactive astrocytes are generally associated
with senile plaques, whereas atrophic astrocytes may occur at
early stages and contribute (owing to reduced synaptic cover-
age and overall homeostatic capabilities) to early cognitive
deficits [139].
rstb.royalsocietypublishing.org
plasticity contribute to learning and memory. In neuropathol-
ogy, astrocytes may undergo reactivity and degeneration,
which are specific to the disease context and may, to a
large extent, define pathological progression.
Competing interests. We declare we have no competing interests.
Funding. The work of A.V. was supported by the Wellcome Trust, by
Alzheimer’s research foundation (UK) and by the Federal Target Pro-
gram ‘Research and development in the priority areas of the

Phil. Trans. R. Soc. B 371: 20150428

8. Conclusion
Astrocytes are principal homeostatic cells of the central ner-
vous system. They evolved through specialization and
diversification of function and assumed the responsibility
for all homeostatic needs of the brain. Astroglial cells are
development of the scientific and technological complex of Russia
for 2014– 2020’ of the Ministry of Education and Science of Russia,
contract 14.581.21.00.16 (Project ID RFMEFI158115X0016). M.N. is
supported by Joint Programme-Neurodegenerative Disease Research
(JPND) project funded by the European Union’s Horizon 2020 research
and innovation programme under grant agreement No. 643417
(DACAPO-AD).

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