Neurons and Plasticity: What Do Glial Cells Have To Do With This?

Michel Condemine & Nicolangelo Iannella : Neurons and Plasticity: what do glial cells have to do with this?
—
Chap. 0 — 2016/7/27 — 16:22 — page 1
Introduction
Synapses, neurons, and neural circuits have long been associated as the entities where
plastic synaptic changes can be observed to take place. These changes rely on the ac-
tivation of biochemical processes within subcellular compartments of the synapses
between neurons as a result of stimulation and associated neural activity. They can
occur on either the pre-synaptic or post-synaptic side of the synapse, or both. This as-
sociation between stimulus inducing neuronal activity and synaptic change has been
the subject of many studies that have shown the involvement of both neural activity
and calcium [1, 2, 3]. Such studies have primarily been driven by the “assumed” mi-
croscopic structure of the synapse. In its basic form, this structure views the synapse
as being composed of two pieces in close proximity to each other; namely the pre-
synaptic terminal and the post-synaptic spine. This complex is commonly referred
to as the synapse. When the synapse is activated by a strong electrical signal called
an action potential or spike, this triggers neurotransmitters, such as glutamate, to be
released from internal stores within the pre-synaptic terminal and expelled into the
space between the pre- and post-sides called the synaptic cleft. Released neurotrans-
mitter then quickly drifts, binds, and unbinds with receptors located on the of the
post-synaptic spinehead. This binding and unbinding triggers the activation of a set
of biochemical signaling cascades that also generates small electrical signals observ-
able in the cell body (soma) of the recipient neuron. When this process of activity
and synaptic transmission occurs regularly it can lead to observable structural and
functional changes in electrical and biochemical responses. This is the outcome of
synaptic plasticity.
Despite the strong focus on neurons and neural communications, the brain is not
simply composed of neurons alone. There are non-neuronal cells in the brain that are
known to be present, such as Astrocytes, Oligodendrocytes, and Ependymal cells.
These non-neuronal cells are collectively called glial cells and have been estimat-
ed to make up about half of the human brain. Tomography studies have shown that
the human brain is composed of 86 billion neurons and an equal number of glial
cells [4, 5]. Historical experiments on glial cells set out to establish whether these
cells produced electrical signals similar to those seen in neurons, but observed and
established that these cells are essentially electrically inert. This led many to believe
that glial cells were not major players in the processing of information in the brain
and probably played the role of neuronal maintenance. Consequently, in most neu-
rology and neuroscience textbooks, glial cells are often stated as cells that make sure
that both neurons and the synaptic connections between neurons in cortical circuits
are maintained in a physiologically healthy state but play no role in the processing of
information in the brain [6, 7, 8]. Glial cells are typically known as the glue with in
the brain that keeps neurons in place. To this end, these cells have largely been ig-
nored when investigating the formation and refinement of cellular functional proper-
ties. Since the turn of the century, however, evidence has begun to emerge indicating
that glial cells may not behave as the brain’s passive elements but play more subtle
yet active roles. Here, we review glial cell physiology, followed by a discussion of
neural-glial signaling and current efforts in modeling neural-glial communications
Nicolangelo Iannella & Michel Condemine: Neurons and Plasticity: what do glial cells have to do with this? —
Chap. 0 — 2016/7/27 — 16:22 — page 2
and potential roles that glia may play in synaptic plasticity and brain function.
Glial cell types
Sometimes called “the other half of the brain”, Glia are non-neuronal cells that are
commonly known to be responsible for maintaining the biochemical balance in the
brain and keeping neurons in a physiologically healthy state. There are four main
types of glial cell in the central nervous system (brain) with another three different
types in the peripheral nervous system. The first type of glial cell is called an As-
trocyte that is typically found in the central nervous system (CNS) [9, 10, 11]. This
sub-type has a characteristic star-shaped morphology with branching processes that
extend and wrap around the synapses of connecting neurons [11]. Astrocytes can
be further divided into two types, fibrous and protoplasmic. Fibrous astrocytes are
typically found in the brain’s white matter and have long thin branches while pro-
toplasmic astrocytes are found in grey matter and have highly branched processes
that are thicker and shorter than their fibrous counterparts [12, 13, 14]. The second
type of glial cell found in the CNS is called Oligodendrocytes. These are cells that
coat the axons of neurons to form the myelin sheath and provides electrical insu-
lation to axon resulting in faster propagation of action potentials (spikes) from one
pre-synaptic neuron to a post-synaptic recipient [15, 16]. The third type is known as
the Ependymal cell and are primarily found forming a lining in the brain’s ventricu-
lar system and the spinal cord’s central canal [17]. They have a unique morphology
where their apical surface are covered by two types of protrusions called microvillia
and layer of organelles forming eyelash like extensions from the apical surface called
cilia [17]. These protrusion allow the cell the absorb and circulate cerebrospinal fluid
(CSF) throughout the brain [18, 19]. The final type of glial cell in the brain are called
Radial glia, which are derived from neuroepithelial cells during neurogenesis [20].
During nervous system development, radial glia act in dual roles by providing a scaf-
fold for newly generated neurons to migrate into and further act as neuronal progen-
itor cells [21]. In the developed brain, radial glia can be found in the retina (M uller
glia) [22] and the Cerebellum (Bergmann glia) [23], since they have migrated (af-
ter loosing their branching attachments) to the surface of the cortex where most will
transform themselves into astrocytes via the process of gliogenesis [24].
Glial Cell function
Glia are known to play many roles in the CNS where some simply provide physical
support to neurons while other are actively involved in supporting and nutrifying the
biochemical environment around neurons and synapses and maintain brain homeo-
statis [11]. They are also known to be involved in creating the micro-architectures in
the brain, provide the brain with the necessary infrastructure to store and distribute
energy to neurons, control the growth and development of neuronal axons and den-
drites [25]. Furthermore they take part in both synaptogenesis and synaptic mainte-
Chap. 0 — 2016/7/27 — 16:22 — page 3
nance and provide the brain as a whole with a biochemical defence system against
chemical and immunological perturbations [25].
Historically thought of as just “gap fillers”, Astrocytes are now known to play a
multitude roles [25]. The first of these roles is their involvement in establishing the
brain’s micro-architecture where through a process called “tiling”, which leads to
the formation of many structural subunits, that are nearly independent of each other,
through the subdivision of protoplasmic astrocytes in the grey matter [26]. These
cells occupy their own region and create sub-anatomical domains within the spa-
tial extent of their branching processes [27, 12]. Within this region the astrocyte’s
membrane covers both synaptic connections and neuronal membranes [28, 25, 29].
Furthermore, some of their branching processing also connect to the walls of nearby
blood vessel, thus establishing a structural neuron-astrocyte-blood vessel complex
commonly called the neurovascular unit [29, 30]. These individual domains also
integrate themselves through gap junctions (electrical synapses) located on periph-
eral branch locations to form superstructures called astroglial syncytia [31, 32]. This
does not result in the formation of one superstructure, but in turn, these syncytia are
structurally segregated being formed within defined anatomical structures, like an
individual somatosensory cortical barrel [31, 32].
Due to their strategic location enveloping synapses, astrocytes are well placed to
control the biochemical environment around neurons [28, 15]. Astrocytes proactive-
ly control the concentration of potassium K+ in the extracellular space surrounding
the synapse and neuron, and are therefore responsible for extracellular K+ home-
ostasis in the brain [28, 33]. Due to astrocyte’s internal molecular machinery, they
can also simultaneously control the flow and concentration of water, various ions,
neurotransmitters, and metabolites within this neurovascular complex [31, 32]. Ex-
periments have shown that K+ concentration is under the direct control of astrocytes.
Under normal physiological conditions, neural activity increases K+ concentration
from 3 mM at rest to a maximum of ≈ 12 mM, while pathological conditions K+
concentration can surpass higher values [34]. From a biophysical viewpoint using the
Goldman-Hodgkin-Katz relation, the increased extracellular K+ concentration can
change the reversal potential of potassium channels and modulate the overall resting
potential of the cell [35]. Astrocytes, however, directly control the K+ concentration
levels since they possess several mechanisms to remove K+ . The first is a passive
mechanism where K+ is taken up at location of high concentration through inward
rectifying K+ channels and spatially redistributed at site with lower concentration
values through the same astrocyte or the coupled astrocytic network [32, 31]. The
second is an active mechanism where removal of excess K+ takes place through the
Na+ -K+ pump that is powered by adenosine triphosphatase (ATP) activity resulting
in an increase in intracellular K+ concentration [32].
An important physiological function performed by astrocytes is the regulation of
glutamate in the extracellular space. When activity dependent release of glutamate
results in an excess, glutamate, despite being critical for neuronal signaling, then ad-
versely acts as a neurotoxin leading to neuronal cell death. Fortunately, astrocytes
possess powerful machinery that can remove up to 80% glutamate from the extra-
cellular space [36]. They achieve this through excitatory amino acid transporters
Chap. 0 — 2016/7/27 — 16:22 — page 4
(EAAT); specifically EAAT1 and EAAT2 are exclusively expressed in astrocytes

where these glutamate transporter mechanisms utilize the energy stored via the trans-
membrane Na+ gradient so that the efflux of one K+ ion and the influx of 3 Na+ ions
and one H+ ion provides the energy to transport a single glutamate molecule. This
in turn leads to an increase in intracellular Na+ but is counterbalanced by efflux
through Na+ -Ca2+ exchanger. Note that both of these molecular mechanisms are
co-localized in the astrocyte’s membrane [36, 26]. Astrocytes further assist in the
homeostatis of glutamatergic transmission via a biochemical process that acts as a
glutamate-glutamine transportation mechanism. Astrocytes enzymatically convert
glutamate into glutamine via astrocytically derived glutamine synthetase. Fortunate-
ly, neurotranmitter receptors are not responsive to glutamine, which is not toxic to
neurons and can be safely transported through extracellular space to pre-synaptic ter-
minals. Glutamine is then absorbed back into the terminal where, once internalized,
it is converted into glutamate to be re-used by the pre-synaptic neuron to signal other
neurons [36, 26].
Another import role played by astrocytes is that they play a central role in the neu-
rovascular complex where local blood flow and metabolic support for neural circuits
are integrated together. Blood vessels in the brain are covered by the branching end-
feet processes while the remaining branching processes of the astrocyte target the
neuronal membrane, synapse, or axon. In this situation the astrocyte can be viewed
as a gateway between the vascular and neural systems [36]. Sensory inputs to neurons
increases their activity and consequently triggers an increase in the concentration of
intracellular calcium Ca2+ in astrocytes. This Ca2+ response can be interpreted as
an integrating signal for the neurovascular complex and ultimately leads to the release
of biochemical compounds that regulate blood flow [36]. Moreover, the readout sig-
nal that is captured during magnetic resonance tomography originates from astrocyte
activity [37, 38]. Furthermore, astrocytes are the only cells in the CNS that act as
a battery or energy storage buffer by synthesizing glycogen, thus providing neurons
with localised metabolic support where neurons can uptake glycogen, release it’s in-
ternalized glucose, and converts this glucose to lactate which consequently provides
neurons with energy‘[36, 37, 38].
**Experiments have additionally shown that astrocytes have a role to play in the
development, maintenance, and stability of synapses and to some degree, can control
the resulting connectivity pattern of neuronal circuits [25, 28]. Astrocytes achieve
this through the production and secretion of biochemical factors that facilitate the
formation of synapses (synaptogenesis). Without these secreted factors synapse for-
mation is greatly depressed since synapse formation critically depends on cholesterol
production and secretation of specific proteins from astrocytes, potentially providing
the raw materials to build new membranes [28]. Astrocytes can also produce fac-
tors that affect specific proteins and signaling cascades critical for the formation and
development of synapses by regulating the density of post-synaptic glutamatergic
Îś-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-Methyl-D-
aspartic acid (NMDA) receptors in spines via the actions of tumour necrosis factor
alpha (TNF-α) and activity-dependent neurotrophic factor (ADNF) produced by as-
trocytes [28].
Chap. 0 — 2016/7/27 — 16:22 — page 5
The astrocyte’s ability to control the formation and maturation synapses places this
cell type a unique position where it can also influence the density of synapses across
neurons by ensheathing areas of neuronal membrane, thus spatially restricting where
synapses can form [39]. Astrocytes also secrete factors like proteolytic enzymes that
react and disassemble the extracellular matrix leading to synaptic pruning where the
astrocyte’s membrane may enter and essentially replace the synapses by isolating the
post-synaptic spine from the presynaptic terminal [28, 39, 16, 15]. Subsequently,
when the brain is in a pathological (diseased) state, the occurrence of this process
can be prominent [16, 25].
Due to their strategic loci, astrocytes are also well placed to modulate the flow of
sensory electrical signals cortical circuits; in the hippocampus they have been shown
to modulate synaptic transmission by suppressing synaptic transmission through the
astrocytic release of ATP and its conversion to adenosine (by hydrolysis with ec-
tonucliotidase) can then bind with neuronal adenosine receptors, resulting in the
inhibition of synaptic transmission [25, 39]. Furthermore, astrocytes can also re-
ceive synaptic inputs as they to have receptors that are activated by neurotransmitters.
Studies have recorded spontaneous “minature” excitatory potentials suggesting that
the sites of neurotransmitter release are in close proximity [15]. Finally, astrocytes
can also trigger the myelinating activity of oligodendrocytes since the activity from
neurons leads to the release of ATP and causes astrocytes to secrete a regulatory
protein called cytokine leukemia inhibitory factor (LIF) that promotes oligodendro-
cyte’s myelination activity. From this point of view, astrocytes can be seen to play a
coordinated executive role [40].
Oligodendrocytes, on the other hand, are the glial cells responsible for myelina-
tion and are found in the white matter of the brain [40, 25]. This glial type also
plays several supporting roles such as aiding the production of trophic factors like
glial cell derived neurotrophic factor (GDNF) and brain derived neurotrophic factor
(BDNF) [41]. These factors are secreted proteins that are involved in the survival of
existing neurons, as well as encouraging the differentiation and growth of new neu-
rons and synapses. Furthermore, oligodendrocytes are primarily responsible for the
creation of myelination across the neuronal membrane. This leads to a reduction of
ion leakage and consequently decreases the capacitance of the neuron’s bilipid mem-
brane [41]. Myelin also leads to a significant increase in transmission speed and
changes the nature of signal propagation from a travelling wave to saltatory (jump-
ing) propagation of action potential spikes occurring at the nodes of Ranvier located
in between the oligodendrocyte derived myelin [35, 42]. This specialization leads
to transmission speeds to be linearly related to the diameter of the axon, whereas
transmission speeds in unmyelinated axons is proportional to the square root of the
diameter [35, 42]. Conversely, satellite oligodendrocytes are found in the grey mat-
ter regions of the brain and regulate the extracellular environment where they remain
close to neurons but do not create myelin sheaths on neuronal membranes [43].
The third type of glial cell present in the CNS are ependymal cells whose sole
purpose is to seeminglessly maintain the homoestatis of Cerebrospinal fluid (CSF)
throughout the brain. Located in the ventricles and the central canal of the spinal
cord, their apical surfaces form a choroid system that regulates CSF so that a rela-
Chap. 0 — 2016/7/27 — 16:22 — page 6
tively constant amount is maintained. Their basal membranes are characterised by

branch like extensions that attach themselves to astrocytes thereby enabling an glial
cell network to be established and provides a substrate by which glial-glial signaling
could, in principle, provide an alternate pathway for neural signals to propagate [44].
The final glial cell type is the Radial Glial cell. The morphology of these cells is
best described as a dipole or bipolar with branches emanating from opposite ends
of the cell body. This particular type of glial cell are known to span wide areas of
cortex during the development period [11, 45, 46]. These cells are interesting as they
act as progenitor cells and go on the produce neurons, astrocytes and oligodendro-
cytes [45, 46, 47, 48]. Radial cells have the ability to divide asymmetrically into a
new glial cell and either a new neuron or an intermediate progenitor daughter cell
(IPC) [46, 47, 48]. Within the subventricular zone, IPCs can go on to further divide
symmetrically in subventricular zone to generate new neurons [48, 49]. Local bio-
chemical cues and their underlying macromolecules have been shown to control how
the radial glial cell subdivides and the type of daughter cells that are made [50]. Bio-
chemical signaling by macromolecules such as Notch and Fibroblast Growth Factor
(FGF) have been shown to play roles in these processes, in particular they regulated
the rate of neurogenesis and consequently the production of both new neurons and
radial glia, which in turn affects the growth, surface area and volumetric expansion
of the cerebral cortex, including the emergence of folds and ridges in the cerebral
cortex [50, 51, 52, 48]. Being confined within the skull, the gyri belonging to this
system of folds and ridges, provides a means to increase the surface area of the brain
without increasing the overall volume, thus limiting brain size [51, 52]. Another
function that radial glial cells possess occurs near the end of cortical development,
where radial glia unattach themselves from the ventricles and migrate toward the
cortical surface to undergo gliogenesis, where most will transform themselves into
astrocytes [51, 52, 49]. In vitro studies suggest that radial glia can also transform in-
to oligodendrocytes via generating oligodendrocyyte progenitor cells. This suggests
that oligodendrocytes are derivatives of radial glia however whether this process ac-
tually occurs in the developing mammalian brain requires more evidence [50, 53].
Signaling in glial cells
Like neurons, astrocytes and other glial cells possess second messenger metabotrop-
ic receptors that are (intrinsically or extrinsically) coupled to specific intracellular
signaling cascades since they are complex biophysical entities that employ many dif-
ferent proteins and macromolecules [10, 27, 54]. These complex biochemical in-
teractions give rise to cellular mechanisms that essentially allows the glial cell to
respond to some external or sensory input. Glial cell responses result from excit-
ing the Endoplasmic Reticulum (ER), leading to an increase in intracellular Ca2+
through the activation of IP3 and Ryanodine receptors [10, 54]. Like the ER of the
neuron, stimulating metabotrophic receptor in glia leads to the production of IP3 ,
resulting in the internalized release of Ca2+ from the ER into the cystol of the glial
cell, producing a measurable calcium signal and hence can be considered as a sub-
Chap. 0 — 2016/7/27 — 16:22 — page 7
strate for glial excitability [27]. These Ca2+ signals are not restricted to a single
glial cell but can propagate through a network of glial cells, connected by connexon
channels or gap junctions, called a glial syncytium [11]. These gap junctions aids
communication between cells to form a Ca2+ wave that travels through the astro-
cytic network, thus potentially providing an alternative communication pathway for
both neurons and glial cells alike [27, 54, 11, 55]. The properties of gap junctions be-
tween neurons has been well studied and provides networks with both a fast means of
neural communication and several important functional properties such as synchro-
nization [42]. By extrapolating these finding, the presence of gap junctions between
glia can potentially provide a potent mix of novel functional attributes and fast cellu-
lar communications within glial networks [54, 56]. This form of communication can
be viewed as a parallel communications channel, however the precise physiological
and functional properties are still to be determined.
Signal transmission from Glial cells
Signal transmission in the brain is typically associated with voltage dependent re-
lease of neurotransmitter from the axon terminals of pre-synaptic neurons that can
quickly diffuse and bind with AMPA and NMDA receptors located in the PSD of
the post-synaptic spine [42]. Experiments have now established that astrocytes and
other glial cell types can also release the same types of transmitters as neurons, such
as glutamate and GABA, into the extracellular space [56, 28, 11]. Consequently,
with the knowledge that glial cells are activated via glutamate from neurons and the
expectation that neurotransmitters released from glia into the extracellular space of
the synaptic cleft can depolarise a post-synaptic neuron, provides an additional line
or channel of communication between neurons. In fact, this leads naturally to the
intriguing concept of gliotransmission as an additional line of communication be-
tween neurons [36, 9]. Most of the neurotransmitters released from glial cell are no
different to those released by neurons, such as glutamate, GABA, and ATP, however
there are several that are uniquely from glial cell origin, namely taurine and kinurenic
acid [36]. Mechanisms underlying neurotransmitter release from neuron have been
extensively studied, which leads one ask what types of mechanisms can lead to the
exocytosis or release of transmitters from glial cells? To date there have been several
different confirmed mechanisms that give rise to gliotransmitter release [36].
The first of these mechanisms is gliotransmitter release via transporters, namely
through the exchange and reuptake involving the cystine-glutamate antiporter (or-
ganic anion transporters); the second is via diffusion processes namely through high
permeable channels such as Cl− channels or P2X7 purinoceptors; and finally via the
more familiar mechanism of Ca2+ -dependent exocytosis [26, 56, 57].
Recent experiments have confirmed that astrocytes express an important family
of proteins including synaptobrevin 2, syntaxin 1, and 23 kDa, which are known to
be involved in exocytotic release [7, 58, 36, 59, 26]. Furthermore, the presence of
V-type proton ATPase (V-ATPase) is known to create a proton concentration gra-
dient that drives ATP-based transport of glutamate into internalized vesicles, and
Chap. 0 — 2016/7/27 — 16:22 — page 8
consequently glutamate is ready to be released by ongoing activity at some later

point in time [57, 60, 58]. The presence of the vesicular glutamate transporters (VG-
LUT1,VGLUT2, and VGLUT3) has also been confirmed through immunoelectron
microscopy [36]. Functionally, glutamate release from glial cells, such as astrocytes,
result in detectable responses in neurons that includes the generation of an inward me-
diated NMDA current leading to the elevation of Ca2+ concentration in the recipient
neuron and furthermore, glial-originating glutamate can alter neuronal excitability
through the modulation of synaptic transmission leading to the synchronization of
neural activity [57, 61]. One must keep in mind that on the subject of information
processing in the brain, the role and relevance of glial cells is still controversial and
is clearly the next big frontier for neuroscience that requires further investigation,
in particular how direct and indirect communication between neurons via glial cells
alters the function or neuronal circuits [62].
A Synaptic Ménage à Trois: The Tripartite synapse concept
Given that glial cells, including astrocytes, typically wrap themselves around both
the pre- and post-synaptic terminals, are known to release glutamate and respond to
glutamatergic inputs. This sets up a unique biological structure where cell-to-cell
communication can potentially be both functionally richer and allow neural com-
munication to proceed on different timescales simultaneously [9, 63, 64]. The close
proximity of the glia to both pre- and post-synaptic membranes has been observed for
much of the brain, including both gray and white matter [28]. For example, in hip-
pocampus 57% of axonal-to-dendritic synapses are covered by glial membranes [28]
(in this case the membrane of astrocytes) where there has been a clearly noticed
tendency that between 60 100% of large synapses to be covered by such membranes
while for small (and probably less functionally active) synapses this percentage range
drops to approximately 40 60% [65]. In the olfactory bulb of the rat the number of
synapses that are covered by glia membrane is over 60% [34]. Interestingly, in the
Glomerular layer, single excitatory synapses that were covered by glial membrane
stood at 27%, while that ratio more than doubled (to 72 %) for reciprocal synaps-
es [34]. Similar numbers of glial covered reciprocal synapses in the external periform
layer also stood 76% [34]. Furthermore, such glial-synaptic contacts can also illus-
trate unique patterning as observed in the cerebellum where virtually all the synaptic
contacts onto Purkinje cell dendrites that originate from parallel fibers are surrounded
by the membranes of Bergmann glial cells [27]. It has been found that an individual
Bergmann glial cell can contact and enwrap 2000 to 6000 parallel fiber-Purkinje cell
synapses [27].
The physical organization of tripartite synapses is such that the individual mem-
branes contributed by both glial cell and neurons are in close proximity to each oth-
er [28]. Their close apposition allows the glial cell membrane to be exposed to
the same set of neurotransmitters that post-synaptic neuronal membranes are sub-
ject to [36, 26, 66, 28]. In this context the glial cell could be viewed as eavesdrop-
ping on the messages transmitted between neurons. From the physiological point
Chap. 0 — 2016/7/27 — 16:22 — page 9
of view, the membranes of glial cells, e.g. astrocytes, possess a family of recep-
tors similar to their neuronal neighbor that respond to various neurotransmitters and
can elicit an calcium based response to presynaptic activity [66, 11]. This similarity
in the types of receptors expressed in both glial cells and their neuronal neighbors
in a given brain region is observed throughout the brain including the basal gan-
glia, cerebral cortex, and the cerebellum [28]. Despite this similarity within a given
region of the brain, these region-based set of receptors are not homogeneous or in-
variant across the entire brain, but change across different brain regions [57]. This
raises an interesting question as to why these closely positioned membranes share
near identical sets of neurotransmitter sensitive receptors and what are the functional
consequences of such features. The addition of a glial membrane into the tradition-
al picture of synapse being a dual membrane complex composed of a pre-synaptic
terminal ending and the post-synaptic membrane (spine head) naturally leads to the
notion of the tripartite synapse, forming a trimembrane complex that contains the
three equally important aforementioned constituents. This construct permits synaps-
es to literally communicate to its receiving membranes in a parallel manner where
neurotransmitter released from the terminal activates the appropriates receptors in
both the glial and post-synaptic neuronal membranes. This leads to the generation
of an electrical signal in the post-synaptic neuron and a (slower) calcium signal in
the glial cell [28, 57]. Ultimately this calcium signal can lead to the release of neu-
rotransmitter which will modulate the activity of (pre-synaptic and post-synaptic)
neuronal membranes [26, 36, 9, 57].
The significant question the neuroscience community is beginning to ask is
whether glia (astrocytes included) play critical active roles in information pro-
cessing. Experiments have established that signaling in glia operates on a slower
timescale, typically of the order of seconds to minutes, than fast electrical signaling
in (and between) neurons [11]. The consequences of this dichotomy of signaling
on information processing and the dynamics and function of neural circuits in the
brain is currently not known, but some attempts have begun to investigate these is-
sues both experimentally and computationally [57, 28]. From the experimental side,
we know that glia are involved in synaptic plasticity however its not clear whether
they play a direct or more of a modulatory role in forming functional neural cir-
cuits [28, 65, 67]. Furthermore, their involvement in synaptic transmission has now
started to cast questions with regards to the role of glia in brain function specifically
the operation of functional networks, despite originally being thought of playing no
role in neurotransmission [7, 67]. Since various receptors in glia can be directly
activated by neurotransmitter released into the extracellular space of the synaptic
cleft in response to some stimuli, coupled with their ability to release neurotransmit-
ters, thus providing an additional signal to the post-synaptic membrane, raises many
questions of their role and functional consequences of reciprocal signaling between
neurons and glia at the level of neural populations [36, 60, 64]. This issue has largely
been unexplored. From the computational side, glia and their slower calcium-based
response could play one of two different roles. The first is that the glial cell simply
behaves as an temporal integrator (a low pass filter in time) where the resulting
calcium signal is simply integrating its own inputs and feeds this signal back into
Chap. 0 — 2016/7/27 — 16:22 — page 10
10
the neuron [68, 68, 63]. The second role is that the glial cell may behave more as
a modulator, by keeping the synapse (and consequently the neuron) in a preferred
operational range of activity [61]. Another property that they provides is spatial
specificity of synaptic transmission in the sense that glial membranes can physically
minimize or stop synaptic spillover of neurotransmitter onto neighboring synapses
on dendrites, thus increasing the degree of spatial precision or conversely isolate a
synapse from receiving interference from the extracellular environment [34, 69, 65].
Despite these roles at the synaptic level, the consequence of glial cell actions on
neurons at the level of functional neural populations remains largely unexplored,
however some theoretical studies have begun to investigate the actions and conse-
quences of neural-glial signaling on neuron and network responses [70, 71, 72, 73].
Investigating the impact of neural-glial signaling on network dynamics
Discovering the currently unknown roles played by glia in the operation of functional
neuronal populations will benefit from the synergy of experimental and theoretical
techniques, typically known as data-driven science [74]. In such a situation where
only a few facts are known, theoretical and computational techniques can be used to
provide predictions that can be tested experimentally [74]. These methodologies will
play important roles in clarifying the roles played by glia in brain. To this end, there
have been some modeling efforts to help understand how glia, and in particular as-
trocytes, influence the dynamics of networks of spiking neurons [75, 76, 72, 73, 77].
Such models are invariably more complex than typical studies of network dynamics
of spiking neurons as the communication between neuron and glia requires a min-
imum of three variables, namely neuronal depolarization (voltage), release of neu-
rotransmitters, and calcium. Note that in order to generate meaningful predictions
requires a description of how glial cells respond to neuronal input and visa-versa.
Here, the efforts from two independent groups of Sosnovtseva [75, 76, 72, 73] and
Jung [78, 79, 80], have made it possible to begin investigating neural-glial signaling
in neural populations computationally. We now present a relatively simple model-
ing framework that can be used as a starting point for studying the influence of glial
cells on the neuronal populations. This model is based upon the known biophysics
but is more complex due to the need to capture the correct nature of communication
between glia and neurons. We start by presenting a standard biophysically inspired
model of the neuron, then the dynamics of the glial cell, and formulate their recip-
rocal interaction. There are a number of neuron models that one can choose from
ranging the Izhikevich model [81] through to detailed biophysical models that con-
tain a variety of ion channels including calcium channels and their own calcium based
subsystem.
As a starting point, one can model a network of neurons using the IzhekevichâĂŹs
model [81] described by
dv
= 0.04v 2 + 5v + 140 − u + Iinput + Iglial
dt
Chap. 0 — 2016/7/27 — 16:22 — page 11
11
du
= a(bv − u)
dt
if v > vthres
then v → vreset
u→u+d
where a = 0.02, b = 0.2, d = 8, vthres = 30, vreset = −65, Iinput represents

the synaptic current generated by post-synaptic receptors, such as AMPA or Gamma-
aminobutyric acid (GABAA ) receptors, that are triggered by inputs originating from
other neurons in the neural population, and Iglial current generated from glia cell
inputs. Both AMPA and GABAA are functionally described by
X
Iinput (t) = Wi g i (t)(EAMPA,GABAA − v)
i " ! !#
i
X (t − tij ) (t − tij )
g (t) = exp − − exp − H(t − tij ),
j
τd τo
where g i (·) is the total conductance to the synapse, tij is the arrival time of the jth
incoming spike from neuron i to the recipient neuron, Wi is the corresponding synap-
tic weight, EAMPA,GABAA represents the reversal potential for AMPA and GABAA ,
H(·) is the Heaviside step function, τo and τd are the onset and decay time constants,
respectively. Although the corresponding conductances for these inputs sum linearly,
there are other synaptic currents whose underlying conductances do not, thus sum-
ming in a nonlinear manner. These types are the NMDA, which is dependent on the
post-synaptic voltage in a nonlinear fashion and the G-protein activated metabotroph-
ic gamma-aminobutyric acid GABAB can also be used in simulations.
In order to be computationally efficient, the glial cell calcium signal response was
adopted from [82], and behaves as a simple integrator of its inputs, given by the
following set of equations [61, 83]:
d[Ca2+ ] X
= −ϕ + σj δ(t − tj )
dt j
dϕ
= α β Ca2+ − ϕ ,

dt
where φ is a recovery variable and σj is assumed to be the neuronal spike input to
the glial cell. This captures the glial cell’s ability to respond to the release of
glutamate from pre-synaptic neurons, δ(·) represent the arrival time of the spike,
and α = 0.001 and β = 0.01 are constants so that they reproduce the slow time
course of calcium change observed in experiments by Kawabata et al (1996) [84].
Glutamate released from glial cells is triggered by the elevation of calcium that is
described by a simple first order process where glial cell glutamate release occurs
Chap. 0 — 2016/7/27 — 16:22 — page 12
12
when calcium concentration exceeds a threshold as described below [82, 61],

− [glu] + Ca2+ − Ca2+ thres − κλ





d[glu] 
if Ca2+ > Ca2+ thres

µ =
dt 



− [glu] − κλ

Otherwise
dλ
η = −λ + [glu]
dt
where [Ca2+ ]thres = 0.0018 mM, κ = 200 is the coupling time constant between
glutamate and the recovery variable λ, µ and η are time constants with values 0.5 s
and 10 s, respectively. The glial current Iglial generated in the neuron is related to the
calcium concentration of the glial cell, which is given by the following experimentally
determined relationship first derived and quantified by Nadkarni and Jung [80, 78].
 2+
 2.11log Ca − 196.69
if Ca2+ > 196.96 nM


Iglial =


0

otherwise
These aforementioned equations provides a computationally efficient starting point
to investigate how glial cells may influence neuronal population.
Glia and Plastic change
Glia and synaptic plasticity
Having experimentally confirmed that at tripartite synapses, signaling between the

neuron and the glial cell is reciprocal in nature where the glial cell can respond to neu-
ronal inputs while concomitantly modulating synaptic transmission, through the ac-
tion of active transporters (complex transport systems) of neurotransmitter molecules
and by releasing molecules known to alter synaptic transmission such as ATP and D-
serine [57]. It is the glial cell’s ability to release molecules that play a role in alter-
ing synaptic transmission and/or the connection itself has prompted questions about
their functional role during synaptic plasticity. One such molecule that is synthe-
sized and released by glial astrocytes is D-serine, a macromolecule known to serve
as a coagonist of NMDA receptors, a post-synaptic receptor ubiquitously for its in-
volvement in synaptic plasticity [57]. A recent experiment has clarified how D-serine
impacts NMDAR induced long term potentiation (LTP) formed by the Schaffer col-
lateral synapses in the CA1 region of the hippocampus [85]. Using Ca2+ chelators to
block increases in the intracellular Ca2+ concentration of glial astrocytes abolishes
the induction of LTP and leads to decreased NMDAR currents at nearby synapses.
Henneberger et al. (2010) illustrated that under these conditions, the addition of D-
serine would rescue LTP induction. Furthermore, by blocking D-serine synthesis
in astrocytes through the inhibition of its enzymatic serine racemase in conjunction
Chap. 0 — 2016/7/27 — 16:22 — page 13
13
with high frequency stimulation that leads to the depletion of available D-serine also
suppresses LTP.
D-serine is not the only substance to influence synaptic plasticity. ATP and it
hydrolyzed version adenosine have also been shown to affect synaptic plasticity out-
comes. Two photon Ca2+ imaging studies of hypothalamic neurons have revealed
that glia-derived ATP leads to synaptic scaling of glutamate based currents in a multi-
plicative fashion by activating purigenic P2X receptors [86]. The underlying process
is dependent on group 1 mGluR1 activation in astrocytes, which leads to an increase
in intracellular Ca2+ concentration from internal stores via IP3 production and leads
to the release of ATP and adenosine into the synaptic cleft‘[86, 57]. For Schaffer
collaterals and their synapses in CA1, the accumulated adenosine can act on adeno-
sine 1 receptors (A1 R), which suppresses glutamate release from the pre-synaptic
terminal resulting in an increase in dynamic range for LTP induction [57]. Both ATP
and adenosine are capable of diffusing to other synapses thus providing a cross-talk
mechanism by depressing glutamate release and synaptic transmission [87]. Another
important protein is glial derived cytokine tumor-necrosis factor-α (TNF-α) which
has been shown to increase the expression in AMPA receptors in hippocampal cul-
tures and suggests that TNF-α may have a role to play in NMDA receptor mediated
LTP and LTD [88]. In the hippocampus, this protein is known to directly contribute
to the process of synaptic scaling, which allows a neuron to globally adjust the synap-
tic efficacy of all its excitatory and inhibitory synapses in response to alterations of
prolonged activity [88, 89]. Experiments have shown that the mechanism behind
these adjustments is the result of increasing the surface expression of AMPA recep-
tors in excitatory synapses, while simultaneously decreasing the efficacy of inhibitory
synapses by decreasing GABAA receptor expression [88, 90, 89]. Moreover, it has
been shown that bidirectional control of synaptic strength is regulated by at least two
opposing signals, with TNF-α increasing the level of excitation while reducing in-
hibition and other signals like brain-derived neurotrophic factor (BDNF) decreasing
the amount of excitation while increasing inhibition [88].
Glia, through the poorly understood actions of glial-derived GABA and glycine,
have been shown play a role in shaping synaptic transmission and plasticity at in-
hibitory synapses. The GABA transporters GAT1, expressed in both neurons and
glia, and GAT3 (only expressed in glial cells) have illustrated that they play an im-
portant role in glial GABA uptake in vivo thus controlling the extracellular levels
of GABA in the synapse [91]. Work with GAT3 knockout mice has illustrated that
this knockout are more resistant to induced seizures since they require higher doses
of GABAA antagonist, when compared to normal wild type mice, before experienc-
ing a seizure [92]. Furthermore, modifying GABA uptake by genetic removal of the
glycine transporter GlyT1 (mainly expressed in brain stem and spinal cord glia) led to
severe motor and respiratory defects [93, 94]. Together these observations highlight
that glial cells play critical roles in synaptic transmission and plasticity.
Glutamate uptake in glial cells is also involved in the modulation of synaptic plas-
ticity through the activity of two (high affinity) excitatory amino acid transporter
subtypes (GLAST/EAAT1) and (GLT1/EAAT2) found on the glial membrane close
to excitatory synapses [57]. These glial transporters prevent both over accumulation
Chap. 0 — 2016/7/27 — 16:22 — page 14
14
of glutamate and over-stimulation of glutamate receptors thus preventing toxic lev-

els of extracellular glutamate to accumulate, hence avoiding excititoxic cell death of
neurons to occur [95, 96]. These transporters are regulated by EphA, an member
of the Eph receptor tyrosine kinase family and their associated ephrin ligands [97].
This signaling system is bidirectional in nature and hence can reverse the roles of
Eph and ephrin, since a Eph receptor can act as a ligand and similarily a ephrin can
act as a receptor [97]. Reports have illustrated that Eph receptor signaling plays a
role in development of dendritic spines, where Ephrin-B ligands activate dendritic
EphB receptors led to spine morphogenesis and maturation while the activation of
EphA receptors are important for regulating spine morphology of pyramidal cells in
adult hippocampus [96]. Experiments have also shown that activation of EphA4 re-
duces both the density and length of dendritic spines whereas loss of EphA4 activity
has the opposite effect [96]. A recent study has illustrated that the ephrin-A3 lig-
and found in astrocytes is critical in maintaining EphA4 activation and normal spine
morphology in vivo [96, 95, 97]. Notably, LTP at CA3-CA1 synapses is modulated
by EphA4 in the postsynaptic CA1 neuron and its corresponding ligand, ephrin-A3,
found in astrocytes [95]. Additionally, increased GLT1 expression in astrocytes and
regulation of GLT1 transcription at mossy fiber (MF)-CA3 synapses led to marked
deficits in mGluR-dependent LTD, suggesting that GLT1 participated in preventing
activation of rep-synaptic receptor [98]. Taken together these findings suggest that
neuronal EphA4 and glial ephrin-A3 signaling can control synapse morphology and
the expression of glial glutamate transporters, thus providing an important mech-
anism that allows astrocytes to bidirectionally regulate both neuronal function and
synaptic plasticity [96, 99, 57].
Glia and structural plasticity
During early development, synapses are excessively established but are later elim-
inated in an activity dependent manner to form functional circuits. Synapses are
dynamic objects that undergo structural remodeling via constant formation and elim-
ination of dendritic spines [100, 101]. Despite implicating neural activity as the pre-
cursor to change, the underlying cellular and molecular processes that lead to such
structural changes in the brain is poorly understood. Recent studies have shown that
glial cells can play an important role in eliminating synapses including neural debris,
such as clearing away fragmented axons and lipid membranes left over from synaptic
elimination [102]. Significantly, in vitro studies using purified retinal ganglion cells
isolated rodent retina have shown that specific biochemical signals derived from glia
play a role in synapse formation (synaptogenesis) [102]. Barres, 1995 [103] showed
that few synapse are formed when rentinal ganglion cells are cultivated in serum-free
media, whereas in the presence of astrocytes or a astrocyte conditioned medium, their
numbers dramatically increased by tenfold and five to sevenfold for these respective
preparations, where newly formed synapses are free from defects and possess func-
tional AMPA receptors. Using this preparation, previous studies have uncovered that
astrocytes secrete three different biochemical factors. The first factor induces the
formation of silent synapses (normal synapse but postsynaptically lacking AMPA
Chap. 0 — 2016/7/27 — 16:22 — page 15
15
receptors). The second, those that increase pre-synaptic activity and increases neu-
rotransmitter release probability. Finally, those that lead to the insertion of glutamate
receptors (such as AMPA) and thus an increase in synaptic weight [104].
Using conditioned cultures, thrombospondins (TSPs) have been identified as one
of these secreted proteins and belongs to the family of large extracellular matrix pro-
teins, which gives rise to an increase in the number of silent synapses [104]. Remov-
ing TSPs from astrocyte conditioned medium reduces synaptogenic activity leading
to fewer synapses being formed. This illustrates that TSPs are both necessary and
sufficient for the formation of new synapses in vitro. At an early postnatal age in-vivo,
TSP1 and TSP2 are expressed in developing astrocytes at the time of synaptogene-
sis, but their expression is downregulated in adults [28]. Significantly, experiments
have shown that mice which lack these proteins had fewer excitatory synapses, high-
lighting that TSPs are important signaling proteins for in-vivo excitatory synapse
formation and structural plasticity. TSP binds to the α2 δ − 1 subunit of voltage
dependent calcium channels (its corresponding neuronal receptor) [102]. Eroglu &
Barres [105] have illustrated that, for all five types of TSP in mammalian brain,
synapse formation can be induced when TSP binds to the type 2 epidermal growth-
factor-like repeats of the von Willebrand factor type A (vWFA) domain in the α2 δ−1
subunit [105]. These authors further postulated that the interaction between TSP and
the α2 δ − 1 subunit activates a synaptogenic signaling complex, that may involve
calcium channels, and gives rise to new synapses to be formed. Furthermore, TSPs
have been shown to bind with another family of macromolecules important for reg-
ulating both the size and function os synapses, called Integrins [105, 106]. Recent
studies have further implicated TSP1 as a ligand for the synaptic adhesion molecule,
neuroligin [106] and highlights that TSPs may have the ability to form and modulate
synaptic function, both pre- and post-synaptically. In an additional twist, in vitro ex-
periments have also shown that the neurontin drug gabapentin can bind to the α2 δ−1
subunit and block the formation of TSP-induced excitatory synapses without affect-
ing established contacts [105]. Furthermore, gabapentin can also disrupt excitatory
synapse formation between neurons throughout brain by blocking the ability of TSP
to bind with the α2 δ − 1 subunit, which triggers synapse formation [105] and pro-
vides additional evidence that glial cells, such as astrocytes, can effectively promote
synapse formation in the in vivo brain.
As TSP secreted from astrocytes only instructs the synapse formation, there must
naturally be other secreted macromolecular signals that facilitate glutamate receptor
insertion into the PSD of the post-synaptic spine membrane, hence allowing astro-
cytes to control synaptic efficacy and function. The precise factors responsible for
AMPA receptor insertion into the post-synaptic membrane in the in vivo mammalian
brain are not well known, however in vitro studies have shown that adding apolipopro-
tein E bound to cholesterol to cultured RGC led to two observable changes. These
cholesterol-induced changes were firstly, a 69% increase in the number of excita-
tory synapses and finally a 12-fold increase in (excitatory) presynaptic transmitter
vesicle release [107, 108]. Both cholesterol and apolipoprotein E increases synaptic
responses in autaptic synapses in cultured RGC by increases in pre-synaptic function
and dendritic differentiation [107, 108]. This suggests as potential role for cholesterol
Chap. 0 — 2016/7/27 — 16:22 — page 16
16
during brain development of the mammalian brain in vivo.
Glia and brain dysfunction
Brain dysfunction, such as stress related disorders, dementia, or Alzheimer’s, and the
development of effective treatments has been identified as an international priority
area that, if left untouched, will cost the world economy trillions of dollars in care
and treatment. Understanding the root causes and development of brain dysfunction
or disease will be critical in avoiding or developing effective long term treatments
for such medical conditions. At the core of understanding the pathology of brain
disease lies the fact that brain activity will not be the same when comparing normal
to pathological conditions. This places the glial cell in a unique position since, as
stated earlier, they can influence network activity as well as alter the excitability of
single neurons, making them targets for developing new treatments. Such gliocentric
approaches to brain dysfunction has the potential to transform our understanding of
the development and treatment of these disorders.
Current literature has illustrated that glia, including astrocytes, are important for
the development, maintenance, and refinement of neural circuits [28, 57, 16, 25].
Hence it stands to reason that any impact on their pathology is likely to have a dra-
matic effect on normal brain function, potentially leading to some disorder in the
brain. For this reason glia, in particular, astrocytes are becoming the focus for under-
standing brain dysfunction such as autism, anxiety, and depression, as these seem to
be closely linked to the physiological state of glia [25]. Recent research has started to
investigate how astrocyte dysfunction contributes to the emergence of synapse based
disorders like autism and schizophrenia. Significantly, developmental diseases like
Down’s syndrome and Fragile X syndrome have illustrated that astrocyte dysfunction
contributes to such disorders.
Down’s Syndrome
In the case of Down’s syndrome, cognitive deficits have been linked to altered number
of spines, specifically experiments have demonstrated that Hippocampal cells grown
in the presence of astrocytes from Down’s syndrome patients resulted in reductions
in spine activity and density [109]. Garcia et al., 2010 [109] has identified that the
level of TSP1, an astrocyte secreted factor known to modulate spine numbers, was
markedly lower in astrocytes from Down’s syndrome patients. The same study fur-
ther showed that restoration of TSP1 levels rescued both spine number, function, and
densities. Thus demonstrating that astrocyte secreted factors contribute to synaptic
defects and suggests that TSP1 may be used as a specific treatment.
Fragile-X Syndrome
Another disease that is associated with cognitive deficits is fragile-X syndrome. Sim-
ilar to Down’s syndrome, fragile-X is caused by the mutation of the Fragile X men-
Chap. 0 — 2016/7/27 — 16:22 — page 17
17
tal retardation 1 (FMPR1) gene which encodes the RNA-binding macromolecule

fragile-X mental retardation protein (FMRP) and is only found in synaptic apparatus
where ribosomes transcribe mRNA into FMRP [39, 110]. Polyglutamine repeats in
the FMR1 gene leads to a loss of FMRP expression in synapses. This has been shown
in FMR1 knockout mice whose phenotype captures many of the physiological and
clinical traits displayed by Fragile X [110, 111]. Furthermore, Hippocampal neurons
grown in the presence of FMR1 deficient astrocytes show reduced spine density and
abnormal dendritic morphology, however such effects are significantly reversed when
neurons from FMR1 deficient mice are growth on a monolayer of normal wild-type
astrocytes [110]. These experiments indicate that astrocyte dysfunction plays a role
leading to abnormal synaptic and dendritic development, and further highlights the
possibility that in vivo defects in spine development are related to abnormal neural-
glial signaling.
Rett Syndrome
Rett syndrome is another developmental disorder that is known to be caused by the

loss of transcriptional repressor methyl-CpG-binding protein 2 (MECP2) [112]. Ex-
periments with mice that lacked the MECP2 gene illustrated many of the same fea-
tures of the human variant of the disease including cognitive impairment, respiratory
abnormalities, and a decrease in brain mass and volume. This suggests that there is
both an important role (along with a critical window) for MECP2 function during
postnatal development [112, 113]. A recent study which cultured normal or wild-
type hippocampal neurons with astrocytes from MECP2 deficient astrocytes lead to
dendrites with stunted dendritic morphologies, suggesting that astrocytic deficits in
MECP2 impair normal dendritic growth [112, 113]. This is further supported by the
in vivo observation that reactivation of MECP2 in astrocytes can partially rescue the
development of neuronal dendrites in MECP2 deficient mice [111]. These findings
raise an interesting question of whether MECP2 controls gene transcription of astro-
cyte secreted proteins involved in normal brain development and thus MECP2 loss
could impair the production and secretion of synaptogenic proteins from astrocytes
and lead to structural deficits in dendritic morphologies akin to those observed in
Rett syndrome.
Epilepsy
Epilepsy is another common neurological disease that affects millions of people

worldwide with 80% of cases occurring in developing countries where the rates
of new cases being detected are up to 140 per 100,000 people [114]. This brain
disorder is typically characterized by the onset of involuntary seizures that vary
from brief and near undetectable episodes to long periods of shaking. The precise
cause of epilespy is not known but there are those that have developed the condi-
tion through brain injury, stroke, brain tumors, brain infections, and birth defects. In
most cases, epileptic seizures result from excessive neural activity in the cerebral cor-
tex [115, 116, 117, 118]. In about 70% of cases epilepsy can be controlled through
Chap. 0 — 2016/7/27 — 16:22 — page 18
18
medication or other relatively inexpensive means. For the remaining 30% of cases
that do not respond to medication then other options include dietary changes and
surgery are also options to help manage the condition [114].
The relationship between seizure states and glial cell activity has recently been
studied with increased scrutiny where immune system responses and activation of
glia are known take part in both the human form of the disorder and in animal mod-
els [119, 120, 121, 122, 123]. It is the link between astrocyte activity to immune
system responses that has caught the interest of many. Astrocytes like other glial
cells are known to be involved with this regulation and they also regulate the perme-
ability of blood brain barrier [124, 125, 126, 127, 25]. In epilepsy patients, however,
the regulation of permeable compounds through the blood brain barrier is impaired
and may have been caused via a number of different avenues like trauma and autoim-
mune disorders [55]. Specifically, in the case following brain injury either through
stroke or head injuries results in the upregulation of adhesion molecules leading to
an increase in proinflammatory cytokines like IL-1β [55]. Furthermore, in patients
that have a genetic susceptibility to brain inflammation are also linked to an increased
risk of developing epilepsy [55]. Significantly, astrocytes, like other glial cells, are
potentially a source of stored Ca that can influence synaptic transmission, thus by
biochemical reduction of calcium signaling in astrocytes may provide a novel thera-
peutic target for future treatments and medication [25].
Parkinson’s disease
Parkinson’s disease (PD) is a progressive yet chronic neurodegenerative disorder that

targets the brain’s motor functions and is characterized by involuntary tremors, pos-
ture instability, reduced mobility and control of limbs. To date, the standard treatment
this disorder has been to administer the dopamine precursor L-DOPA. In patients, this
compound is known to reduce the majority of symptoms but can have some severe
side effects [128, 129, 130]. For these reasons, research in PD is focusing to obtain
a detailed understanding of biochemistry underlying this complex brain disorder so
that new treatments aimed at either slowing or stopping the advancement of PD can
be developed while minimizing side effects.
PD research has demonstrated that there is a glial component to the disease which
has been observed in both PD patients and animal models of the condition. Recent
studies have shown that glial cells can play either a protective role or a destructive one
on dopaminergic neurons depending on a glial cells activated state [131, 132, 133].
Specifically, astrocytes produce neurotrophic factors like GDNF which supports the
survival and growth of dopaminergic neurons located in the striatum [134]. Dur-
ing neurodegeneration, oxidative stress leads to increases in reactive oxygen species
(ROS) that ultimately leads to degeneration of dopaminergic neurons and detectable
macromolecular changes in the substantia nigra. The affects of ROS can be reduced
by an enzyme called glutathione peroxidase. This compound is normally present
in astrocytes located in the mesencephalon and can essentially stop the reaction of
transforming hydrogen peroxide to hydroxyl based radicals [135, 136, 137, 138]. The
precise roles and mechanisms of glutathione peroxide in PD are currently unknown.
Chap. 0 — 2016/7/27 — 16:22 — page 19
19
Another source of ROS production in the substantia nigra of PD patients origi-

nates from autoxidation processes that leads to the loss of dopamine [138]. A novel
in vitro study illustrated that astrocytes have the necessary molecular machinery to
deal with ROS internally and thus effectively protecting neurons from the effects of
ROS. This study showed that astrocytes that contain enzymes that destroy dopamine,
like monoamine oxidase type B, also possess glutathione peroxidase. This allows
the astrocyte to deal with ROS agents intracellularly without significant impact on
neurons [139]. However, this seemingly protective nature of glia is not clear cut
but could be state dependent. This is supported by studies illustrating that glial
cells respond to inflammation by producing known chemical compounds: cytokines,
prooxidant reactive compounds, and prostaglandin, all of which are known to dam-
age neurons [140]. In this regard, inflammatory responses of glial cells assists the
progression of the disorder. Other chemical imbalances of glial origin are present
in PD patients, such as higher expression levels of TNF-α, INF-γ and IL-1β and
elevated expression levels of IL-2, IL-4, and IL-6 (proinflammatory cytokines) in
the basal ganglia, thus suggesting increased cytokine production associated with the
progression of PD [141, 142, 143]. These are not the only chemical imbalances in
PD, the upregulation in the expression of major histocompatibility complex (MHC)
molecules like HLA-DR positive microglia and β 2-microglobulin has also been ob-
served [144]. To complicate matters further, the involvement cytokines such as TNF-
α, IL-1β , and IFN-γ are strong activators of nitric oxide synthase production in glia,
ultimately leading to increased expression of CD23, the low affinity immunoglobulin
E receptor [145]. Moreover, CD23 is strongly expressed in the substantia nigra of
PD patients but not in healthy control subjects [134]. Furthermore, nitric oxide can
also lead to iron released from the ferritin protein, thus adding a toxic component
as well as increased formation of hydroxyl radicals [136, 25]. Overall it seems that
glial cell activity and cytokine production are delicately balanced where overproduc-
tion of cytokines leads to oxidative stress, which ultimately leads to the activation of
proapoptotic signaling pathways and cell death in dopaminergic neurons, thus aiding
the progression of PD.
Alzheimer’s disease
Another brain disorder that is gaining more attention is Alzheimer’s disease as its
commonly associated with the elderly resulting in age-related cognitive decline char-
acterized by progressive deficits in short term memory, cognitive impairment and
changes in personality. Alzheimer patients are known to have greatly reduced brain
mass (more than 35 % in weight), where affected areas include the limbic system and
the temporal lobe of the cerebral cortex. The molecular pathways responsible for this
condition are currently unknown, however histological studies have suggested that an
over production of β -amyloids, a macromolecule known to adversely affect specific
biochemical signaling pathways that leads to the phosphorylation of the τ protein
and the acceleration of the condition, in addition to other cellular changes including
mitochondrial dysfunction. This has become known as the "amyloid cascade hypoth-
esis" [146, 147, 148]. Furthermore, there seems to be a link between the production
Chap. 0 — 2016/7/27 — 16:22 — page 20
20
of β -amyloids and the activity of microglia and astrocytes.

Changes to amyloid precursor proteins through genetic mutation leads to increased
production of β -amyloid-42 (Aβ -42) peptide; and this in turn gives rise to amyloid
induced neurotoxicity that includes oxidative stress, free radical formation, and in-
flammation in the brain [149]. The complex nature underlying the onset and progres-
sion of Alzheimer’s disease lies in how environmental and genetic factors combine
and interact over time, resulting in multiple alteration to the underlying biochemistry
of the brain that is not attributable to any single mechanism. Many genes have been
connected to Alzheimer’s disease but the apolipoprotein E 4 (APOE-4) gene has
attracted attention since patients bearing this gene have been connected to a 50%
increase in risk of developing Alzheimer’s [149]. Notably, APOE is acknowledged
to be a protein that is involved in the development and repair of the brain primarily
made and secreted by astrocytes. This raised the question whether astrocyte dys-
function contributed to the advance of Alzheimer’s disease. In particular, it was
believed that the APOE-4 isoform reduced the astrocyte’s ability to capture and in-
ternalize (phagocytosis) deposits of β -amyloids, hence allowing Alzheimer’s disease
to progress [150]. However, recent experimental data has presented a controversy.
Some studies have demonstrated that astrocytes take part in the protection of neurons
by degrading and clearing β -amyloids deposits [151]. Whereas other data has shown
that astrocytes responses to chronic stress increases β -amyloids deposits through the
overexpression of β -secretase and provides a scaffold for combining APP with γ -
secretase, thus allowing the progression of the disease [150].
Other studies have additionally linked the genesis of Alzheimer’s disease to inflam-
matory processes. Notably the response to increased levels of β -amyloids leads to
both astrocytes and microglia to protect neurons, but in turn, also leads to the release
cytokines which can alter and even impair the function of neurons and contribute
to their degeneration [152, 153]. Furthermore, astrocyte dysfunction could degrade
the operation of the blood brain barrier. This adversely influences β -amyloid pro-
duction in glia via clearance through transport processes involving the receptor for
advanced glycation end products (RAGE) and the LDL-receptor-related protein 1
(LRP1), as they both play important roles in balancing the clearance and production
of β -amyloids [154, 155]. Alzheimer patients are known to have altered relative dis-
tributions of these receptors. Finally, Alzheimer’s patients have altered calcium sig-
naling in both neurons and glia. Due to the importance of calcium in regulating bio-
chemical signaling in both neurons and glia, including neuronal excitability, changes
to calcium will ultimately impact neural-glial signaling, especially the generation of
calcium waves in glia which forms the basis of communication between neurons and
glial cells permitting glia, including astrocytes, to modulate neural activity. In-vitro
studies involving cultured astrocytes have shown that the addition of β -amyloid in-
creases both the amplitude and velocity of evoked calcium waves [156, 157]. This
consequently leads to changes in the messages being communicated between neurons
and glia, which may eventually give rise to a pathological state.
Chap. 0 — 2016/7/27 — 16:22 — page 21
21
Conclusions
We have seen that glial cells, once thought to be the substance that keeps neurons in
place and the brain together, are now being viewed as complex biochemical compo-
nents that not only help protect neurons from various forms of biochemical pertur-
bations, but they also involved in neuronal regulation and synaptic plasticity. Glial
cell involvement in immune system responses adds an additional level of complex
dynamics, however its their constant communication with neurons and their ability
to regulate the activity of synapses on different timescales that neural-glial signaling
is starting to be viewed as an important contributor toward information processing
in the brain. The precise actions of glia in both synaptic plasticity and information
processing in the brain still needs to be fully elucidated, however it is their immune
system responses in both normal and dysfunctional states that is starting to attract
increased scientific attention, as it seems that biochemical signaling provided by glia
may infact provide unique pathways and treatments for a range of conditions and
disorders that are targeted, and at the same time minimize any negative impact on
neurons and functional circuits in general.
In order to better understand the glial cell actions on neurons and the nervous sys-
tem in general, especially with respect to information processing, the development
of new mathematical and computational models/techniques will play a pivotal role in
understanding the significance of neural-glial signaling for synaptic plasticity, cor-
tical development, and information processing in the brain. Such future theoreti-
cal/computational studies will provide novel insights that experimentalists can check
to verify or debunk model predictions. Significantly, at this instant in time, theoretical
models of cortical network dynamics and development that consider neural-glial sig-
naling are few and far between, however future theoretical and computational studies
are expected to provide novel predictions especially in the area of brain dysfunction
and aid data-driven development of new yet novel treatments.
Acknowledgments
N. Iannella’s contribution was supported by the People Programme (Marie Curie

Actions) of the European Unions Seventh Framework Programme (FP7/2007-2013)
under REA grant agreement No PCOFUND-GA-2012-600181.
Chap. 0 — 2016/7/27 — 16:22 — page 22
22
2016/7/27 — 16:22 — page 23
23
References
1 Rose, C.R. and Konnerth, A. (2001) Neuroglia: definition, classification,

Stores not just for storage: intracellular evolution, numbers, development. glial
calcium release and synaptic plasticity. physiology and pathophysiology, pp.
Neuron, 31 (4), 519–522. 73–104.
2 Zucker, R.S. (1999) Calcium-and 10 Verkhratsky, A. and Butt, A.M. (2013)
activity-dependent synaptic plasticity. Glial physiology and pathophysiology,
Current opinion in neurobiology, 9 (3), John Wiley & Sons.
305–313. 11 Laming, P.R. and Syková, E. (1998) Glial
3 Shouval, H.Z., Bear, M.F., and Cooper, cells: their role in behaviour, Cambridge
L.N. (2002) A unified model of nmda University Press.
receptor-dependent bidirectional synaptic 12 Bushong, E.A., Martone, M.E., Jones,
plasticity. Proceedings of the National Y.Z., and Ellisman, M.H. (2002)
Academy of Sciences, 99 (16), Protoplasmic astrocytes in ca1 stratum
10 831–10 836. radiatum occupy separate anatomical
4 Azevedo, F.A., Carvalho, L.R., Grinberg, domains. The Journal of neuroscience,
L.T., Farfel, J.M., Ferretti, R.E., Leite, 22 (1), 183–192.
R.E., Lent, R., Herculano-Houzel, S. et al. 13 Miller, R.H. and Raff, M.C. (1984)
(2009) Equal numbers of neuronal and Fibrous and protoplasmic astrocytes are
nonneuronal cells make the human brain biochemically and developmentally
an isometrically scaled-up primate brain. distinct. The Journal of neuroscience,
Journal of Comparative Neurology, 4 (2), 585–592.
513 (5), 532–541. 14 Oberheim, N.A., Wang, X., Goldman, S.,
5 Snell, R.S. (2010) Clinical neuroanatomy, and Nedergaard, M. (2006) Astrocytic
Lippincott Williams & Wilkins. complexity distinguishes the human brain.
6 Kang, J., Jiang, L., Goldman, S.A., and Trends in neurosciences, 29 (10),
Nedergaard, M. (1998) 547–553.
Astrocyte-mediated potentiation of 15 Allen, N.J. and Barres, B.A. (2005)
inhibitory synaptic transmission. Nature Signaling between glia and neurons: focus
neuroscience, 1 (8), 683–692. on synaptic plasticity. Current opinion in
7 Bacci, A., Verderio, C., Pravettoni, E., and neurobiology, 15 (5), 542–548.
Matteoli, M. (1999) The role of glial cells 16 Allen, N.J. and Barres, B.A. (2009)
in synaptic function. Philosophical Neuroscience: gliaâĂŤmore than just
Transactions of the Royal Society B: brain glue. Nature, 457 (7230), 675–677.
Biological Sciences, 354 (1381), 403–409. 17 Spassky, N., Merkle, F.T., Flames, N.,
8 Kurosinski, P. and Götz, J. (2002) Glial Tramontin, A.D., García-Verdugo, J.M.,
cells under physiologic and pathologic and Alvarez-Buylla, A. (2005) Adult
conditions. Archives of neurology, ependymal cells are postmitotic and are
59 (10), 1524–1528. derived from radial glial cells during
9 Verkhratsky, A. and Butt, A. (2013) embryogenesis. The Journal of
2016/7/27 — 16:22 — page 24
24
Neuroscience, 25 (1), 10–18. neuron–glia interaction: parallel fiber

18 Abney, E.R., Bartlett, P.P., and Raff, M.C. signaling to bergmann glial cells. Nature
(1981) Astrocytes, ependymal cells, and neuroscience, 2 (2), 139–143.
oligodendrocytes develop on schedule in 28 Eroglu, C. and Barres, B.A. (2010)
dissociated cell cultures of embryonic rat Regulation of synaptic connectivity by
brain. Developmental biology, 83 (2), glia. Nature, 468 (7321), 223–231.
301–310. 29 Eroglu, C., Barres, B.A., and Stevens, B.
19 Schnitzer, J., Franke, W.W., and (2008) Glia as active participants in the
Schachner, M. (1981) development and function of synapses, in
Immunocytochemical demonstration of Structural and functional organization of
vimentin in astrocytes and ependymal the synapse, Springer, pp. 683–714.
cells of developing and adult mouse 30 Metea, M.R. and Newman, E.A. (2006)
nervous system. The Journal of Cell Glial cells dilate and constrict blood
Biology, 90 (2), 435–447. vessels: a mechanism of neurovascular
20 Hartfuss, E., Galli, R., Heins, N., and coupling. The Journal of neuroscience,
Götz, M. (2001) Characterization of cns 26 (11), 2862–2870.
precursor subtypes and radial glia. 31 Verkhratsky, A. and Toescu, E. (2006)
Developmental biology, 229 (1), 15–30. Neuronal-glial networks as substrate for
21 Anthony, T.E., Klein, C., Fishell, G., and cns integration. Journal of cellular and
Heintz, N. (2004) Radial glia serve as molecular medicine, 10 (4), 869–879.
neuronal progenitors in all regions of the 32 Giaume, C., Koulakoff, A., Roux, L.,
central nervous system. Neuron, 41 (6), Holcman, D., and Rouach, N. (2010)
881–890. Astroglial networks: a step further in
22 Bringmann, A., Pannicke, T., Grosche, J., neuroglial and gliovascular interactions.
Francke, M., Wiedemann, P., Skatchkov, Nature Reviews Neuroscience, 11 (2),
S.N., Osborne, N.N., and Reichenbach, A. 87–99.
(2006) Müller cells in the healthy and 33 Dani, J.W., Chernjavsky, A., and Smith,
diseased retina. Progress in retinal and S.J. (1992) Neuronal activity triggers
eye research, 25 (4), 397–424. calcium waves in hippocampal astrocyte
23 Levitt, P. and Rakic, P. (1980) networks. Neuron, 8 (3), 429–440.
Immunoperoxidase localization of glial 34 Higashi, K., Fujita, A., Inanobe, A.,
fibrillary acidic protein in radial glial cells Tanemoto, M., Doi, K., Kubo, T., and
and astrocytes of the developing rhesus Kurachi, Y. (2001) An inwardly rectifying
monkey brain. Journal of Comparative k+ channel, kir4. 1, expressed in
Neurology, 193 (3), 815–840. astrocytes surrounds synapses and blood
24 Bonni, A., Sun, Y., Nadal-Vicens, M., vessels in brain. American Journal of
Bhatt, A., Frank, D.A., Rozovsky, I., Physiology-Cell Physiology, 281 (3),
Stahl, N., Yancopoulos, G.D., and C922–C931.
Greenberg, M.E. (1997) Regulation of 35 Hille, B. et al. (2001) Ion channels of
gliogenesis in the central nervous system excitable membranes, vol. 507, Sinauer
by the jak-stat signaling pathway. Science, Sunderland, MA.
278 (5337), 477–483. 36 Verkhratsky, A. and Kirchhoff, F. (2007)
25 Barres, B.A. (2008) The mystery and Glutamate-mediated neuronal–glial
magic of glia: a perspective on their roles transmission. Journal of anatomy,
in health and disease. Neuron, 60 (3), 210 (6), 651–660.
430–440. 37 Figley, C.R. and Stroman, P.W. (2011)
26 Kettenmann, H. and Verkhratsky, A. The role (s) of astrocytes and astrocyte
(2011) Neuroglia, der lebende nervenkitt. activity in neurometabolism,
Fortschritte der Neurologie· Psychiatrie, neurovascular coupling, and the
79 (10), 588–597. production of functional neuroimaging
27 Grosche, J., Matyash, V., Möller, T., signals. European Journal of
Verkhratsky, A., Reichenbach, A., and Neuroscience, 33 (4), 577–588.
Kettenmann, H. (1999) Microdomains for 38 Gordon, G.R., Choi, H.B., Rungta, R.L.,
2016/7/27 — 16:22 — page 25
25
Ellis-Davies, G.C., and MacVicar, B.A. (2009) The glial nature of embryonic and
(2008) Brain metabolism dictates the adult neural stem cells. Annual review of
polarity of astrocyte control over neuroscience, 32, 149.
arterioles. Nature, 456 (7223), 745–749. 51 Rash, B.G., Lim, H.D., Breunig, J.J., and
39 Clarke, L.E. and Barres, B.A. (2013) Vaccarino, F.M. (2011) Fgf signaling
Emerging roles of astrocytes in neural expands embryonic cortical surface area
circuit development. Nature Reviews by regulating notch-dependent
Neuroscience, 14 (5), 311–321. neurogenesis. The Journal of
40 Ishibashi, T., Dakin, K.A., Stevens, B., Neuroscience, 31 (43), 15 604–15 617.
Lee, P.R., Kozlov, S.V., Stewart, C.L., and 52 Rash, B.G., Tomasi, S., Lim, H.D., Suh,
Fields, R.D. (2006) Astrocytes promote C.Y., and Vaccarino, F.M. (2013) Cortical
myelination in response to electrical gyrification induced by fibroblast growth
impulses. Neuron, 49 (6), 823–832. factor 2 in the mouse brain. The Journal
41 Bradl, M. and Lassmann, H. (2010) of Neuroscience, 33 (26), 10 802–10 814.
Oligodendrocytes: biology and pathology. 53 Mo, Z. and Zecevic, N. (2009) Human
Acta neuropathologica, 119 (1), 37–53. fetal radial glia cells generate
42 Kandel, E.R., Schwartz, J.H., Jessell, oligodendrocytes in vitro. Glia, 57 (5),
T.M., Siegelbaum, S.A., and Hudspeth, A. 490–498.
(2000) Principles of neural science, 54 Reuss, B. and Unsicker, K. (2005),
vol. 4, McGraw-hill New York. Neuroglia. kettenmann, h.; ransom, br.,
43 Baumann, N. and Pham-Dinh, D. (2001) editors.
Biology of oligodendrocyte and myelin in 55 Ricci, G., Volpi, L., Pasquali, L., Petrozzi,
the mammalian central nervous system. L., and Siciliano, G. (2009)
Physiological reviews, 81 (2), 871–927. Astrocyte–neuron interactions in
44 Johansson, C.B., Momma, S., Clarke, neurological disorders. Journal of
D.L., Risling, M., Lendahl, U., and biological physics, 35 (4), 317–336.
Frisén, J. (1999) Identification of a neural 56 Perea, G. and Araque, A. (2005) Glial
stem cell in the adult mammalian central calcium signaling and neuron–glia
nervous system. Cell, 96 (1), 25–34. communication. Cell calcium, 38 (3),
45 Rakic, P. (1971) Neuron-glia relationship 375–382.
during granule cell migration in 57 Paixão, S. and Klein, R. (2010)
developing cerebellar cortex. a golgi and Neuron–astrocyte communication and
electonmicroscopic study in macacus synaptic plasticity. Current opinion in
rhesus. Journal of Comparative neurobiology, 20 (4), 466–473.
Neurology, 141 (3), 283–312. 58 Auld, D.S. and Robitaille, R. (2003) Glial
46 Rakic, P. (1972) Mode of cell migration to cells and neurotransmission: an inclusive
the superficial layers of fetal monkey view of synaptic function. Neuron, 40 (2),
neocortex. Journal of Comparative 389–400.
Neurology, 145 (1), 61–83. 59 Kettenmann, H., Verkhratsky, A. et al.
47 Rakic, P. (1988) Specification of cerebral (2008) Neuroglia: the 150 years after.
cortical areas. Science, 241 (4862), Trends in neurosciences, 31 (12), 653.
170–176. 60 Achour, S.B. and Pascual, O. (2012)
48 Rakic, P. (2009) Evolution of the Astrocyte–neuron communication:
neocortex: a perspective from functional consequences. Neurochemical
developmental biology. Nature Reviews research, 37 (11), 2464–2473.
Neuroscience, 10 (10), 724–735. 61 Pasti, L., Volterra, A., Pozzan, T., and
49 Doetsch, F., Caille, I., Lim, D.A., Carmignoto, G. (1997) Intracellular
García-Verdugo, J.M., and calcium oscillations in astrocytes: a
Alvarez-Buylla, A. (1999) Subventricular highly plastic, bidirectional form of
zone astrocytes are neural stem cells in communication between neurons and
the adult mammalian brain. Cell, 97 (6), astrocytes in situ. The Journal of
703–716. neuroscience, 17 (20), 7817–7830.
50 Kriegstein, A. and Alvarez-Buylla, A. 62 Pfrieger, F.W. (2010) Role of glial cells in
2016/7/27 — 16:22 — page 26
26
the formation and maintenance of networks. Journal of biological physics,

synapses. Brain research reviews, 63 (1), 35 (4), 425–445.
39–46. 73 Postnov, D., Brazhe, N., and Sosnovtseva,
63 Perea, G. and Araque, A. (2005) O. (2012) Functional modeling of
Properties of synaptically evoked neural-glial interaction, in Biosimulation
astrocyte calcium signal reveal synaptic in Biomedical Research, Health Care and
information processing by astrocytes. The Drug Development, Springer, pp.
Journal of neuroscience, 25 (9), 133–151.
2192–2203. 74 Kell, D.B. and Oliver, S.G. (2004) Here is
64 Araque, A., Parpura, V., Sanzgiri, R.P., the evidence, now what is the hypothesis?
and Haydon, P.G. (1999) Tripartite the complementary roles of inductive and
synapses: glia, the unacknowledged hypothesis-driven science in the
partner. Trends in neurosciences, 22 (5), post-genomic era. Bioessays, 26 (1),
208–215. 99–105.
65 Witcher, M.R., Kirov, S.A., and Harris, 75 Postnov, D.E., Ryazanova, L.S., and
K.M. (2007) Plasticity of perisynaptic Sosnovtseva, O.V. (2007) Functional
astroglia during synaptogenesis in the modeling of neural–glial interaction.
mature rat hippocampus. Glia, 55 (1), BioSystems, 89 (1), 84–91.
13–23. 76 Postnov, D., Ryazanova, L., Brazhe, N.,
66 Verkhratsky, A., Orkand, R.K., and Brazhe, A., Maximov, G., Mosekilde, E.,
Kettenmann, H. (1998) Glial calcium: and Sosnovtseva, O. (2008) Giant glial
homeostasis and signaling function. cell: New insight through
Physiological reviews, 78 (1), 99–141. mechanism-based modeling. Journal of
67 Bolton, M.M. and Eroglu, C. (2009) Look biological physics, 34 (3-4), 441–457.
who is weaving the neural web: glial 77 Amiri, M., Hosseinmardi, N., Bahrami, F.,
control of synapse formation. Current and Janahmadi, M. (2013)
opinion in neurobiology, 19 (5), 491–497. Astrocyte-neuron interaction as a
68 Araque, A., Carmignoto, G., and Haydon, mechanism responsible for generation of
P.G. (2001) Dynamic signaling between neural synchrony: a study based on
astrocytes and neurons. Annual Review of modeling and experiments. Journal of
Physiology, 63 (1), 795–813. computational neuroscience, 34 (3),
69 Wang, X., Lou, N., Xu, Q., Tian, G.F., 489–504.
Peng, W.G., Han, X., Kang, J., Takano, T., 78 Nadkarni, S. and Jung, P. (2004) Dressed
and Nedergaard, M. (2006) Astrocytic neurons: modeling neural–glial
ca2+ signaling evoked by sensory interactions. Physical biology, 1 (1), 35.
stimulation in vivo. Nature neuroscience, 79 Nadkarni, S. and Jung, P. (2005) Synaptic
9 (6), 816–823. inhibition and pathologic hyperexcitability
70 Amiri, M., Montaseri, G., and Bahrami, F. through enhanced neuron-astrocyte
(2011) On the role of astrocytes in interaction: a modeling study. Journal of
synchronization of two coupled neurons: integrative neuroscience, 4 (02), 207–226.
a mathematical perspective. Biological 80 Nadkarni, S. and Jung, P. (2007)
cybernetics, 105 (2), 153–166. Modeling synaptic transmission of the
71 Amiri, M., Bahrami, F., and Janahmadi, tripartite synapse. Physical biology, 4 (1),
M. (2012) Modified thalamocortical 1.
model: A step towards more 81 Izhikevich, E.M. et al. (2003) Simple
understanding of the functional model of spiking neurons. IEEE
contribution of astrocytes to epilepsy. Transactions on neural networks, 14 (6),
Journal of computational neuroscience, 1569–1572.
33 (2), 285–299. 82 Reato, D., Cammarota, M., Parra, L.C.,
72 Postnov, D., Koreshkov, R., Brazhe, N., and Carmignoto, G. (2012)
Brazhe, A., and Sosnovtseva, O. (2009) Computational model of neuron-astrocyte
Dynamical patterns of calcium signaling interactions during focal seizure
in a functional model of neuron–astrocyte generation. Frontiers in computational
2016/7/27 — 16:22 — page 27
27
neuroscience, 6. database (mgd): mouse biology and

83 T Porter, J. and D McCarthy, K. (1997) model systems. Nucleic acids research,
Astrocytic neurotransmitter receptors in 36 (suppl 1), D724–D728.
situ and in vivo. Progress in neurobiology, 93 Doengi, M., Hirnet, D., Coulon, P., Pape,
51 (4), 439–455. H.C., Deitmer, J.W., and Lohr, C. (2009)
84 Kawabata, S., Tsutsumi, R., Kohara, A., Gaba uptake-dependent ca2+ signaling in
Yamaguchi, T., Nakanishi, S., and Okada, developing olfactory bulb astrocytes.
M. (1996) Control of calcium oscillations Proceedings of the National Academy of
by phosphorylation of metabotropic Sciences, 106 (41), 17 570–17 575.
glutamate receptors. Nature, 383 (6595), 94 Gomeza, J., Hülsmann, S., Ohno, K.,
88–92. Eulenburg, V., Szöke, K., Richter, D., and
85 Henneberger, C., Papouin, T., Oliet, S.H., Betz, H. (2003) Inactivation of the glycine
and Rusakov, D.A. (2010) Long-term transporter 1 gene discloses vital role of
potentiation depends on release of glial glycine uptake in glycinergic
d-serine from astrocytes. Nature, inhibition. Neuron, 40 (4), 785–796.
463 (7278), 232–236. 95 Filosa, A., Paixão, S., Honsek, S.D.,
86 Gordon, G.R., Iremonger, K.J., Kantevari, Carmona, M.A., Becker, L., Feddersen,
S., Ellis-Davies, G.C., MacVicar, B.A., B., Gaitanos, L., Rudhard, Y., Schoepfer,
and Bains, J.S. (2009) Astrocyte mediated R., Klopstock, T. et al. (2009) Neuron-glia
distributed plasticity at hypothalamic communication via epha4/ephrin-a3
glutamate synapses. Neuron, 64 (3), 391. modulates ltp through glial glutamate
87 Pascual, O., Casper, K.B., Kubera, C., transport. Nature neuroscience, 12 (10),
Zhang, J., Revilla-Sanchez, R., Sul, J.Y., 1285–1292.
Takano, H., Moss, S.J., McCarthy, K., and 96 Carmona, M.A., Murai, K.K., Wang, L.,
Haydon, P.G. (2005) Astrocytic purinergic Roberts, A.J., and Pasquale, E.B. (2009)
signaling coordinates synaptic networks. Glial ephrin-a3 regulates hippocampal
Science, 310 (5745), 113–116. dendritic spine morphology and glutamate
88 Stellwagen, D. and Malenka, R.C. (2006) transport. Proceedings of the National
Synaptic scaling mediated by glial tnf-α. Academy of Sciences, 106 (30),
Nature, 440 (7087), 1054–1059. 12 524–12 529.
89 Kaneko, M., Stellwagen, D., Malenka, 97 Klein, R. (2009) Bidirectional modulation
R.C., and Stryker, M.P. (2008) Tumor of synaptic functions by eph/ephrin
necrosis factor-α mediates one component signaling. Nature neuroscience, 12 (1),
of competitive, experience-dependent 15–20.
plasticity in developing visual cortex. 98 Omrani, A., Melone, M., Bellesi, M.,
Neuron, 58 (5), 673–680. Safiulina, V., Aida, T., Tanaka, K.,
90 Beattie, E.C., Stellwagen, D., Morishita, Cherubini, E., and Conti, F. (2009)
W., Bresnahan, J.C., Ha, B.K., Up-regulation of glt-1 severely impairs ltd
Von Zastrow, M., Beattie, M.S., and at mossy fibre–ca3 synapses. The Journal
Malenka, R.C. (2002) Control of synaptic of physiology, 587 (19), 4575–4588.
strength by glial tnfα. Science, 99 Rothstein, J.D., Patel, S., Regan, M.R.,
295 (5563), 2282–2285. Haenggeli, C., Huang, Y.H., Bergles,
91 Chiu, C.S., Brickley, S., Jensen, K., D.E., Jin, L., Hoberg, M.D., Vidensky, S.,
Southwell, A., Mckinney, S., Cull-Candy, Chung, D.S. et al. (2005) β -lactam
S., Mody, I., and Lester, H.A. (2005) antibiotics offer neuroprotection by
Gaba transporter deficiency causes increasing glutamate transporter
tremor, ataxia, nervousness, and increased expression. Nature, 433 (7021), 73–77.
gaba-induced tonic conductance in 100 Holtmaat, A. and Svoboda, K. (2009)
cerebellum. The Journal of neuroscience, Experience-dependent structural synaptic
25 (12), 3234–3245. plasticity in the mammalian brain. Nature
92 Bult, C.J., Eppig, J.T., Kadin, J.A., Reviews Neuroscience, 10 (9), 647–658.
Richardson, J.E., Blake, J.A., Group, 101 Trachtenberg, J.T., Chen, B.E., Knott,
M.G.D. et al. (2008) The mouse genome G.W., Feng, G., Sanes, J.R., Welker, E.,
2016/7/27 — 16:22 — page 28
28
and Svoboda, K. (2002) Long-term in Developmental expression of fmrp in the

vivo imaging of experience-dependent astrocyte lineage: implications for fragile
synaptic plasticity in adult cortex. Nature, x syndrome. Glia, 55 (15), 1601–1609.
420 (6917), 788–794. 111 Jacobs, S. and Doering, L.C. (2010)
102 Christopherson, K.S., Ullian, E.M., Astrocytes prevent abnormal neuronal
Stokes, C.C., Mullowney, C.E., Hell, J.W., development in the fragile x mouse. The
Agah, A., Lawler, J., Mosher, D.F., Journal of Neuroscience, 30 (12),
Bornstein, P., and Barres, B.A. (2005) 4508–4514.
Thrombospondins are astrocyte-secreted 112 Chahrour, M. and Zoghbi, H.Y. (2007)
proteins that promote cns synaptogenesis. The story of rett syndrome: from clinic to
Cell, 120 (3), 421–433. neurobiology. Neuron, 56 (3), 422–437.
103 Meyer-Franke, A., Kaplan, M.R., Pfieger, 113 Chahrour, M., Jung, S.Y., Shaw, C., Zhou,
F.W., and Barres, B.A. (1995) X., Wong, S.T., Qin, J., and Zoghbi, H.Y.
Characterization of the signaling (2008) Mecp2, a key contributor to
interactions that promote the survival and neurological disease, activates and
growth of developing retinal ganglion represses transcription. Science,
cells in culture. Neuron, 15 (4), 805–819. 320 (5880), 1224–1229.
104 Elmariah, S.B., Hughes, E.G., Oh, E.J., 114 Organization, W.H. et al. (2013) Fact
and Balice-Gordon, R.J. (2004) sheet n 999: epilepsy. Avalaible:<
Neurotrophin signaling among neurons http://www. who.
and glia during formation of tripartite int/mediacentre/factsheets/fs999/en.
synapses. Neuron glia biology, 1 (04), 115 Lowenstein, D.H. (2009) Epilepsy after
339–349. head injury: an overview. Epilepsia,
105 Eroglu, C., Allen, N.J., Susman, M.W., 50 (s2), 4–9.
O’Rourke, N.A., Park, C.Y., Özkan, E., 116 Annegers, J.F., Hauser, W.A., Coan, S.P.,
Chakraborty, C., Mulinyawe, S.B., Annis, and Rocca, W.A. (1998) A
D.S., Huberman, A.D. et al. (2009) population-based study of seizures after
Gabapentin receptor α2δ -1 is a neuronal traumatic brain injuries. New England
thrombospondin receptor responsible for Journal of Medicine, 338 (1), 20–24.
excitatory cns synaptogenesis. Cell, 117 DeLorenzo, R.J., Sun, D.A., and
139 (2), 380–392. Deshpande, L.S. (2005) Cellular
106 Xu, J., Xiao, N., and Xia, J. (2010) mechanisms underlying acquired epilepsy:
Thrombospondin 1 accelerates the calcium hypothesis of the induction
synaptogenesis in hippocampal neurons and maintainance of epilepsy.
through neuroligin 1. Nature Pharmacology & therapeutics, 105 (3),
neuroscience, 13 (1), 22–24. 229–266.
107 Goritz, C., Mauch, D.H., and Pfrieger, 118 Bhalla, D., Godet, B., Druet-Cabanac, M.,
F.W. (2005) Multiple mechanisms mediate and Preux, P.M. (2011) Etiologies of
cholesterol-induced synaptogenesis in a epilepsy: a comprehensive review. Expert
cns neuron. Molecular and Cellular review of neurotherapeutics, 11 (6),
Neuroscience, 29 (2), 190–201. 861–876.
108 Mauch, D.H., Nägler, K., Schumacher, S., 119 Choi, J. and Koh, S. (2008) Role of brain
Göritz, C., Müller, E.C., Otto, A., and inflammation in epileptogenesis. Yonsei
Pfrieger, F.W. (2001) Cns synaptogenesis medical journal, 49 (1), 1–18.
promoted by glia-derived cholesterol. 120 Uhlmann, E.J., Wong, M., Baldwin, R.L.,
Science, 294 (5545), 1354–1357. Bajenaru, M.L., Onda, H., Kwiatkowski,
109 Garcia, O., Torres, M., Helguera, P., D.J., Yamada, K., and Gutmann, D.H.
Coskun, P., and Busciglio, J. (2010) A (2002) Astrocyte-specific tsc1 conditional
role for thrombospondin-1 deficits in knockout mice exhibit abnormal neuronal
astrocyte-mediated spine and synaptic organization and seizures. Annals of
pathology in down’s syndrome. PLoS neurology, 52 (3), 285–296.
One, 5 (12), e14 200. 121 Coulter, D.A. and Eid, T. (2012)
110 Pacey, L.K. and Doering, L.C. (2007) Astrocytic regulation of glutamate
2016/7/27 — 16:22 — page 29
29
homeostasis in epilepsy. Glia, 60 (8), (2003) The role of glial reaction and
1215–1226. inflammation in parkinson’s disease.
122 Tanaka, K., Watase, K., Manabe, T., Annals of the New York Academy of
Yamada, K., Watanabe, M., Takahashi, Sciences, 991 (1), 214–228.
K., Iwama, H., Nishikawa, T., Ichihara, 133 McGeer, P.L. and McGeer, E.G. (2008)
N., Kikuchi, T. et al. (1997) Epilepsy and Glial reactions in parkinson’s disease.
exacerbation of brain injury in mice Movement Disorders, 23 (4), 474–483.
lacking the glutamate transporter glt-1. 134 Hunot, S., Bernard, V., Faucheux, B.,
Science, 276 (5319), 1699–1702. Boissiere, F., Leguern, E., Brana, C.,
123 Vezzani, A., French, J., Bartfai, T., and Gautris, P., Guerin, J., Bloch, B., Agid, Y.
Baram, T.Z. (2011) The role of et al. (1996) Glial cell line-derived
inflammation in epilepsy. Nature Reviews neurotrophic factor (gdnf) gene expression
Neurology, 7 (1), 31–40. in the human brain: a post mortem in situ
124 Janzer, R.C. and Raff, M.C. (1987) hybridization study with special reference
Astrocytes induce blood–brain barrier to parkinson’s disease. Journal of neural
properties in endothelial cells. Nature, transmission, 103 (8-9), 1043–1052.
325 (6101), 253–257. 135 Sian, J., Dexter, D.T., Lees, A.J., Daniel,
125 Abbott, N.J., Rönnbäck, L., and Hansson, S., Agid, Y., Javoy-Agid, F., Jenner, P.,
E. (2006) Astrocyte–endothelial and Marsden, C.D. (1994) Alterations in
interactions at the blood–brain barrier. glutathione levels in parkinson’s disease
Nature Reviews Neuroscience, 7 (1), and other neurodegenerative disorders
41–53. affecting basal ganglia. Annals of
126 Hawkins, B.T. and Davis, T.P. (2005) The neurology, 36 (3), 348–355.
blood-brain barrier/neurovascular unit in 136 Jenner, P., Dexter, D., Sian, J., Schapira,
health and disease. Pharmacological A., and Marsden, C. (1992) Oxidative
reviews, 57 (2), 173–185. stress as a cause of nigral cell death in
127 Ballabh, P., Braun, A., and Nedergaard, parkinson’s disease and incidental lewy
M. (2004) The blood–brain barrier: an body disease. Annals of Neurology,
overview: structure, regulation, and 32 (S1), S82–S87.
clinical implications. Neurobiology of 137 Desagher, S., Glowinski, J., and Premont,
disease, 16 (1), 1–13. J. (1996) Astrocytes protect neurons from
128 Cotzias, G.C., Papavasiliou, P.S., and hydrogen peroxide toxicity. The Journal
Gellene, R. (1969) Modification of of Neuroscience, 16 (8), 2553–2562.
parkinsonismâĂŤchronic treatment with 138 Desagher, S., Glowinski, J., and Prémont,
l-dopa. New England Journal of J. (1997) Pyruvate protects neurons
Medicine, 280 (7), 337–345. against hydrogen peroxide-induced
129 Barbeau, A. (1969) L-dopa therapy in toxicity. The Journal of neuroscience,
parkinson’s disease: a critical review of 17 (23), 9060–9067.
nine years’ experience. Canadian Medical 139 Kastner, A., Anglade, P., Bounaix, C.,
Association Journal, 101 (13), 59. Damier, P., Javoy-Agid, F., Bromet, N.,
130 Fahn, S. (1986) Recent developments in Agid, Y., and Hirsch, E. (1994)
Parkinson’s disease, Raven Pr. Immunohistochemical study of
131 Jackson-Lewis, V., Vila, M., Tieu, K., catechol-o-methyltransferase in the human
Teismann, P., Vadseth, C., Choi, D.K., mesostriatal system. Neuroscience, 62 (2),
Ischiropoulos, H., Przedborski, S. et al. 449–457.
(2002) Blockade of microglial activation 140 Anglade, P., Vyas, S., Javoy-Agid, F.,
is neuroprotective in the Herrero, M., Michel, P., Marquez, J.,
1-methyl-4-phenyl-1, 2, 3, Mouatt-Prigent, A., Ruberg, M., Hirsch,
6-tetrahydropyridine mouse model of E., and Agid, Y. (1997) Apoptosis and
parkinson disease. The Journal of autophagy in nigral neurons of patients
Neuroscience, 22 (5), 1763–1771. with parkinson’s disease. Histology and
132 Hirsch, E., Breidert, T., Rousselet, E., histopathology, 12 (1), 25–32.
Hunot, S., Hartmann, A., and Michel, P. 141 Mogi, M., Harada, M., Riederer, P.,
2016/7/27 — 16:22 — page 30
30
Narabayashi, H., Fujita, K., and Nagatsu, 148 Hardy, J. and Selkoe, D.J. (2002) The
T. (1994) Tumor necrosis factor-α (tnf-α) amyloid hypothesis of alzheimer’s
increases both in the brain and in the disease: progress and problems on the
cerebrospinal fluid from parkinsonian road to therapeutics. Science, 297 (5580),
patients. Neuroscience letters, 165 (1), 353–356.
208–210. 149 Rocchi, A., Pellegrini, S., Siciliano, G.,
142 Mogi, M., Harada, M., Kondo, T., and Murri, L. (2003) Causative and
Riederer, P., Inagaki, H., Minami, M., and susceptibility genes for alzheimerâĂŹs
Nagatsu, T. (1994) Interleukin-1β , disease: a review. Brain research bulletin,
interleukin-6, epidermal growth factor and 61 (1), 1–24.
transforming growth factor-α are elevated 150 Roßner, S., Lange-Dohna, C., Zeitschel,
in the brain from parkinsonian patients. U., and Perez-Polo, J.R. (2005)
Neuroscience letters, 180 (2), 147–150. Alzheimer’s disease β -secretase bace1 is
143 Mogi, M., Harada, M., Narabayashi, H., not a neuron-specific enzyme. Journal of
Inagaki, H., Minami, M., and Nagatsu, T. neurochemistry, 92 (2), 226–234.
(1996) Interleukin (il)-1β , il-2, il-4, il-6 151 Heneka, M.T. and O’Banion, M.K. (2007)
and transforming growth factor-α levels Inflammatory processes in alzheimer’s
are elevated in ventricular cerebrospinal disease. Journal of neuroimmunology,
fluid in juvenile parkinsonism and 184 (1), 69–91.
parkinson’s disease. Neuroscience letters, 152 Meda, L., Cassatella, M.A., Szendrei,
211 (1), 13–16. G.I., Otvos, L., Baron, P., Villalba, M.,
144 McGeer, P.L., Schwab, C., Parent, A., and Ferrari, D., and Rossi, F. (1995)
Doudet, D. (2003) Presence of reactive Activation of microglial cells by
microglia in monkey substantia nigra β -amyloid protein and interferon-γ .
years after 1-methyl-4-phenyl-1, 2, 3, Nature, 374 (6523), 647–650.
6-tetrahydropyridine administration. 153 Meda, L., Baron, P., and Scarlato, G.
Annals of neurology, 54 (5), 599–604. (2001) Glial activation in alzheimerâĂŹs
145 Dugas, B., Mossalayi, M.D., Damais, C., disease: the role of aβ and its associated
and Kolb, J.P. (1995) Nitric oxide proteins. Neurobiology of aging, 22 (6),
production by human monocytes: 885–893.
evidence for a role of cd23. Immunology 154 Deane, R., Wu, Z., and Zlokovic, B.V.
today, 16 (12), 574–580. (2004) Rage (yin) versus lrp (yang)
146 Strittmatter, W.J., Saunders, A.M., balance regulates alzheimer amyloid
Schmechel, D., Pericak-Vance, M., β -peptide clearance through transport
Enghild, J., Salvesen, G.S., and Roses, across the blood–brain barrier. Stroke,
A.D. (1993) Apolipoprotein e: 35 (11 suppl 1), 2628–2631.
high-avidity binding to beta-amyloid and 155 Farfara, D., Lifshitz, V., and Frenkel, D.
increased frequency of type 4 allele in (2008) Neuroprotective and neurotoxic
late-onset familial alzheimer disease. properties of glial cells in the pathogenesis
Proceedings of the National Academy of of alzheimer’s disease. Journal of cellular
Sciences, 90 (5), 1977–1981. and molecular medicine, 12 (3), 762–780.
147 Tanzi, R.E., Gusella, J.F., Watkins, P.C., 156 Mattson, M.P. and Chan, S.L. (2003)
Bruns, G., St George-Hyslop, P., Neuronal and glial calcium signaling in
Van Keuren, M.L., Patterson, D., Pagan, alzheimerâĂŹs disease. Cell calcium,
S., Kurnit, D.M., and Neve, R.L. (1987) 34 (4), 385–397.
Amyloid beta protein gene: cdna, mrna 157 Mattson, M.P. and Chan, S.L. (2003)
distribution, and genetic linkage near the Calcium orchestrates apoptosis. Nature
alzheimer locus. Science, 235 (4791), cell biology, 5 (12), 1041–1043.
880–884.

Neurons and Plasticity: What Do Glial Cells Have To Do With This?

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Neurons and Plasticity: What Do Glial Cells Have To Do With This?

Diunggah oleh

Hak Cipta:

Michel Condemine & Nicolangelo Iannella : Neurons and Plasticity: what do glial cells have to do with this?

Glial cell types

Glial Cell function

(EAAT); specifically EAAT1 and EAAT2 are exclusively expressed in astrocytes

tively constant amount is maintained. Their basal membranes are characterised by

Signaling in glial cells

Signal transmission from Glial cells

consequently glutamate is ready to be released by ongoing activity at some later

A Synaptic Ménage à Trois: The Tripartite synapse concept

Investigating the impact of neural-glial signaling on network dynamics

where a = 0.02, b = 0.2, d = 8, vthres = 30, vreset = −65, Iinput represents

when calcium concentration exceeds a threshold as described below [82, 61],

Glia and Plastic change

Glia and synaptic plasticity

Having experimentally confirmed that at tripartite synapses, signaling between the

of glutamate and over-stimulation of glutamate receptors thus preventing toxic lev-

Glia and structural plasticity

during brain development of the mammalian brain in vivo.

Glia and brain dysfunction

tal retardation 1 (FMPR1) gene which encodes the RNA-binding macromolecule

Rett syndrome is another developmental disorder that is known to be caused by the

Epilepsy is another common neurological disease that affects millions of people

Parkinson’s disease (PD) is a progressive yet chronic neurodegenerative disorder that

Another source of ROS production in the substantia nigra of PD patients origi-

of β -amyloids and the activity of microglia and astrocytes.

N. Iannella’s contribution was supported by the People Programme (Marie Curie

1 Rose, C.R. and Konnerth, A. (2001) Neuroglia: definition, classification,

Neuroscience, 25 (1), 10–18. neuron–glia interaction: parallel fiber

the formation and maintenance of networks. Journal of biological physics,

neuroscience, 6. database (mgd): mouse biology and

and Svoboda, K. (2002) Long-term in Developmental expression of fmrp in the

Anda mungkin juga menyukai