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Input selectivity via neural-glial signaling

Nicolangelo Iannella
NeuroTek International (Research & Consulting) Pty. Ltd., South Australia
&
Computational and Theoretical Neuroscience Laboratory
School of Information Technology & Mathematical Sciences
Institute for Telecommunications Research
The University of South Australia, Mawson Lakes, Australia
E-mail: nicolangelo.iannella@unisa.edu.au, nicolangelo.iannella@gmail.com

Michel Condemine
Condemine Consulting, Paris, France
E-mail:cc@mcondemine.com

Glial cells including astrocytes are another type of cell that exist in the brain along side neurons. They
have long been thought to play no active role in information processing in the brain especially in the
cerebral cortex. Historically, their role was more to support the physiology well being of neurons also to
provide a medium to support the structure of the brain. Over the past decade, new experimental results
show that glial cells are able to transfer calcium signals with each other and with neurons. Furthermore,
glial cells can also absorb or secrete neural transmitters. This is now forcing a community wide rethink
on the role glial cells play in brain function, including information processing. Due to the glial cell’s prox-
imity to the synapse, tripartate synapses have been proposed and studied computationally. Significantly,
experiments have further shown that glial cells may be involved in the strengthening and weakening of
synaptic strength (synaptic plasticity), however their precise actions during synaptic plasticity are only
now starting to be studied. To this end, it is becoming increasingly important to elucidate the role of
neural-glial signaling during the development of functional properties both at the neural and network
levels. Here, for the first time, we explore how neural-glial signaling and reciprocal calcium/glutamate
cellular communication via tripartate synapses leads to the emergence of input selectivity.

Keywords: Glial cells; neural-glial signaling; Timing-based synaptic plasticity; spiking neurons.

1. Introduction ume.4, 5 Since the turn of this century, evidence has

Glial cells, including astrocytes, have long been
thought of those cells that make sure that neurons
and synaptic connections are physiologically healthy
but play no role whatsoever in neural computation
and information processing in the brain.1–3 These
cells are known to be the “brain glue” that keep
neurons in place. To this end, many experimental
and computational neuroscientist have completely
ignored glial cells when investigating functional prop-
erties and synaptic plasticity, despite these cells mak-
ing up half the human brain by number and vol-
begun to emerge implicating that glial cells, in par-
ticular astrocytes, in the regulation of synaptic trans-
mission and aid neurons to form connections that
give rise to functional neural circuits.6–10
Currently, the function of glial cells are being
reconsidered where there is now sufficient exper-
imental evidence implicating them in active roles
in the brain, such as modulating/regulating synap-
tic transmission.6, 7, 10 Being electrically inert, glial
cell responses are driven by calcium influx/changes
that can result in the generation of a calcium
wave.11–14 Furthermore, astrocytes have been found

1
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to form their own networks linked by gap junctions15
that permit cellular communication via calcium-
based signaling.16 Recent findings have also illus-
trated their involvement in the formation of synapses
(synaptognesis)17–20 as well as synaptic plastic-
ity,7, 21, 22 however the precise loci and mechanisms
are still unknown.
Both synaptic plasticity and glial cell responses
are driven by calcium. In glia, activity in response to
some input manifests itself as non-homogeneous cal-
cium profile over time.11–14, 23–25 While in neurons,
calcium influx triggers a cascade of events that ul-
timately lead to changes in synaptic strength.26–31
Learning rules have been devise based on particu-
lar attributes of both inputs and outputs, such as
rate32–34 and spike timing,35–38 or purely based upon
calcium change (like the BCM model).39–41 Spike
timing-dependent plasticity (STDP) is a timing-
based learning rule that has been investigated both
experimentally and theoretically to help understand
how connections and functionality can be learnt
by neural circuits composed of spiking neurons in-
cluding its relation to calcium-dependent plastic-
ity.33, 35–38 Here, changes in synaptic strength are
a function of the timing difference between post-
synaptic spike generation and the arrival time of
inputs. Notably, potentiation (strengthening of the
synapse) occurs when ∆T = tpost −tpre > 0 while de-
pression (weakening a synapse) occurs when ∆T ≤ 0
and its characterized by two exponentially decaying
windows35, 36, 38 depicted in Fig 1. STDP has previ-
ously been shown that it can solve the input selec-
tivity problem, but only after changing the rule by
replacing the fixed maximal amplitude of the depres-
sion window with a variable maximal amplitude that
changes in an activity-dependent fashion as a func-
tion of the post-synaptic neuron spike activity.42–44
Without this modification input selectivity fails to
emerge.
Synaptic plasticity rules like STDP, typically
have taken into consideration a stereotypic struc-
ture of the synapse consisting of the pre-synaptic
axon terminal and the post-synaptic spine-head. The
strength of a synapse is measured in nS and is pro-
portional to the maximal amount of electrical current
that is generated by a single pre-synaptic input due
to the number of glutamate receptors in the postsy-
naptic density (PSD) of the spine-head. When plas-
ticity leads to depression then the number of gluta-
mate receptors has been reduced while potentiation
leads to an increase in the number of glutamate re-
ceptors in the PSD and thus a larger maximal cur-
rent. Despite this portrayal, the reality is that glia
(astrocyte) is an additional component present at the
synaptic junction.6
×10-3 STDP temporal window
3
Weight change ∆W
2
1
0
-1
-2
-100 -50 0 50
∆ T=tpost-tpre spike interval (ms)
Figure 1. An example of an STDP temporal window,
reproduced from Froemkes45 experiments on rats.
Significantly, experiments have shown that there
is a form of three-way communication between
pre-synaptic and post-synaptic components of the
synapse and glial cells where notably communica-
tion occurs via glutamate release and calcium sig-
naling.7, 12, 15, 46–48 Despite originally thought of as
passive components there is now increasing evidence
that commands a closer look at the roles of glial
cells in information processing and synaptic plastic-
ity.7, 24, 49 Recent theoretical studies have begun to
investigate the role of glial cells in formation pro-
cessing and the impact that they have on neural
function and the behavior of neural circuits.50–65 Re-
cent experiments have further shown that neural-
glial signaling influences synaptic plasticity as well
the state of cortical circuits and their composite neu-
rons.6–10, 23, 24, 66
In this paper, we investigate how neural-glial
signaling impacts timing based learning by studying
the formation of input selectivity. Here, for the first
time, we develop a new hybrid spike-timing learning
rule that explicitly incorporates reciprocal communi-
cation and signaling between an output neuron and
a glial cell. We illustrate that this reciprocal commu-
nication between cell types is critical for input selec-
tivity to emerge as it further provides a more physi-
ologically plausible basis for the approximation used
in pasts studies.43 In the following sections, we de-
scribe both the network topology, the models used to
describe the cellular properties of neurons and glial
cells, and how neural-glial signaling takes place. We
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present our new learning rule that takes advantage
of this reciprocal communication and show that this
new time-based rule can give rise to input selectivity.
We also quantify importance in the efficacy of glial
to neuron signals.
2. Materials and Methods
2.1. Neural Glial Network Topology
We built a network of spiking neurons with a feedfor-
ward network topology. The network itself was com-
posed of an input layer consisting of 100 excitatory
and 20 inhibitory neurons. These neurons would con-
sequentially drive an output neuron and a glial cell.
The membrane potential of the output neuron would
dynamically change over time being driven by its in-
puts and if conditions were favorable then the output
neuron would generate a train of action potentials
in response to its inputs. Furthermore, the glial cell
is also stimulated by the input neurons leading to
changes in calcium activity. As the output neuron
and the glial cell contribute to each others activity
in a reciprocal manner, the glial cell also receives in-
puts from the output neuron and in turn the glial
cell provides an additional calcium driven input to
the output neuron. Excitatory connections originat-
ing from the excitatory neurons of the input layer
were initial set to the same strength but were altered
in an activity-dependent manner as a functions of
spike timing and neural-glial activity. All other con-
nections were fixed.
2.2. Stimulation Paradigm
A set of ten distinct input patterns were used whose
representation was such that they spanned an ab-
stract feature space. These stimuli were used to gen-
erate spike activity in the input neurons. The set of
patterns was constructed to cover our abstract fea-
ture space (without gaps), noting that more input
patterns can be used at the cost of the degree of
overlap between input patterns. The input patterns
were described by a Gaussian profile if finite width,
( )
(x − xc )2
G(x) = Amin + (Amax − Amin ) exp − , the input profile, σ = 10, and Rmin and Rmax are the
2σ 2
where x represents a location of the feature space,
xc is the centre of the input profile, and σ = 10, and
Amin and Amax are the minimal and maximal ampli-
tudes, respectively. For simplicity in representation,
the span of our excitatory input neurons matches the
span of the abstract feature space, so that the first
and last input neurons are located on the boundaries
of the space. The centres are equally spaced within
this feature space and consequentially input patterns
spanned (covered with some overlap between adja-
cent profiles) the entire feature space. To generate
spike activity in the input neurons, a pattern was
randomly selected and then it was presented to the
excitatory neuron which generated spikes via random
processes governed by the rate determined by the in-
put to the neurons. The pattern would stimulate the
excitatory neurons for 200 ms after which a new in-
put pattern was selected and presented to the exci-
tatory input neurons. Inhibitory neurons also gener-
ated spikes randomly at a constant yet fixed mean
rate throughout the simulation. The changes of in-
put patterns continued until the output neuron has
learned to respond selectivity to one of the inputs.
2.3. Neural Models
We used efficient spiking neuron models for the input
neurons to save on computational resources. Excita-
tory input neurons were designed to encode an ab-
stract feature space where each neuron responded se-
lectively to inputs by firing action potentials or spikes
in a distinct yet finite continuous region of this space.
Inhibitory neurons were non selective and provided
a constant level of inhibition to the output neuron.
Specifically, the firing pattern of each input neuron
is generated through a stochastic process where the
rate of spike generation of each excitatory input neu-
ron is determined by an input function described by a
Gaussian (bell-shaped) profile of finite spatial width,
( )
(xi − xjc )2
G(xi ) = Rmin + (Rmax − Rmin ) exp − ,
2σ 2
where xi represents the location of the input neuron
with respect to the feature space, xjc is the centre of
minimal and maximal firing rates, respectively. Note
that we have replaced the amplitudes Amin and Amax
with Rmin and Rmax . Their parameter values were
Rmin = 2 and Rmax = 55, respectively. For an input
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neuron located at the chosen centre the firing rate is where tj is the arrival time of an incoming spike to
maximal. A set of ten inputs spanning an abstract the output neuron, τd and τo are the respective decay
feature space were used to generate spike activity in and onset time constants, H(·) is the Heaviside step
the input neurons. Ten distinct input patterns were function, and Iglial represents the current generated
used as the input that covers our abstract feature by the glial cell in the output neuron.
space, noting that more input patterns can be used A simple glial cell model was adopted from50
at the cost of the degree of overlap between input and was given by the following set of equations:68, 69
patterns. For simplicity in representation the span
of our excitatory input neurons matches the span ∑
d[Ca2+ ]
of the feature space, so that the first and last in- = −φ + σj δ(t − tj )
dt
put neurons are located on the boundaries of the ab- j
stract feature space. The centres are equally spaced
and consequentially input patterns spanned (covered dφ ( [ ] )
= α β Ca2+ − φ ,
with some overlap between adjacent profiles) the en- dt
tire feature space. The connection strengths between
these 20 inhibitory neurons are equal and do not where ϕ is a recovery variable and σj is assumed to be
change, while excitatory connection weights to the the neuronal spike input to the glial cell since they
output neuron were altered during learning. respond to release of glutamate from pre-synaptic
During learning, input neurons stimulated the neurons, δ(·) represent timing of the spike, and α =
output neuron and glial cell by randomly selecting 0.001 and β = 0.01 are constants so that they repro-
an input centre to be active for short time periods duce the slow time course of calcium change observed
of 200 msec after which a new centre (and corre- in experiments by Kawabata et al (1996).70 Gluta-
sponding input neurons) was randomly selected to mate release from glial cells that is triggered by the
stimulate these output cells. This process continues elevation of calcium can be simply described by a
until input selectivity is established and stable. simple first order process where glial cell glutamate
The output neuron was modelled as a regular fir- release occurs when calcium concentration exceeds a
ing neuron using the Izhekevichs model67 described threshold as described below,50, 68
by  ([ ] [ ] )

 − [glu] + Ca2+ − Ca2+ thres − κλ


dv 
= 0.04v 2 + 5v + 140 − u + Iinput + Iglial d[glu]  [ ] [ ]
dt µ = if Ca2+ > Ca2+ thres
dt 

du 

= a(bv − u) 

dt − [glu] − κλ Otherwise
dλ
if v > vthres η = −λ + [glu]
then v → vreset dt
u→u+d
where [Ca2+ ]thres = 0.0018 mM, κ = 200 is the cou-
pling time constant between glutamate and the re-
where a = 0.02, b = 0.2, d = 8, vthres = 30, covery variable λ, µ and η are time constants with
vreset = −65, Iinput represents the current generated values 0.5 s and 10 s, respectively. The current gen-
by synaptic inputs originating from the input neu- erated in the neuron by the glial cell is given by
rons, given by the following experimentally determined relationship
first derived by Nadkarni and Jung59, 61 which relates
∑[ (
(t − tj )
)
current with glial cell calcium concentration.
Iinput = exp −
τd  ([ 2+ ] )
j
( )] 
 2.11[log Ca
] − 196.69
(t − tj ) 
− exp − H(t − tj ), if Ca2+ > 196.96 nM
Iglial =
τo 


0 otherwise
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As an additional feature, I explicitly allowed the glial
cell to alter the neurons recovery variable thus allow-
ing it to change excitability in a homeostatic fashion.
Specifically, the parameter b which appears in the
equation describing the neurons recovery variable u
was allowed to be altered in a activity dependent
fashion exclusively driven by the glial cell.50 The cor-
responding equation is given by
db
= −mIglial + (bs − b).
dt
2.4. Neural-glial Plasticity Rule
Plastic changes in the strength of excitatory synapses
proceeds via the following new learning rule that is
both a function of spike timing and neural-glial ac-
tivity. This new rule can be viewed as an extension
to the original spike timing-dependent plasticity rule
where the amplitude of the depression component of
the window is now a function of the neuron’s instan-
taneous firing rate and the current that is generated
in the neuron by the glial cell. This joint timing-
neural-glial activity drives changes in the weights
of excitatory connections impinging onto the output
neuron. The learning rule is expressed as follows
 neural-glial based rule takes advantage of both spike

 Ap exp (−|∆t|/τ+ ) if ∆t > 0

∆wj =

 −Am (R(t), Iglial ) exp (−|∆t|/τ− )

if ∆t ≤ 0
where ∆t = tpre − tpost denotes the interspike inter-
val (the time difference between the arrival time of an
input tpre and the time when a post-synaptic spike
was generated tpost . Ap is a positive constant and
Am (R(t), Iglial ) is a function of the output neurons
and glial activity, both of which scale the size of indi-
vidual weight changes. The time constants τ+ and τ−
determines the temporal range of the learning win-
dow in which synaptic strengthening and weakening
occurs, whose parameter values are τ+ = τ− = 5 ms.
The maximal amplitude of the depression win-
dow given by the following;
Iglial R(t)
Am (R(t), Iglial ) = 0.15Ad ,
ρptarget rate
where Ad = 0.001125 is a constant, R(t) is a low-pass
filtered version of the output neuron’s firing pattern,
p = 2, and ρneuron is the targert firing rate of the
output neuron.
dR(t) R(t) ρpneuron
=− + ,
dt τR τR
ρneuron = < ρ(t) >
#of post-synaptic spikes
= .
∆T
Note that by changing the maximal amplitude of
the learning rule’s depression window is based on
the assumption that both glial and the output neu-
ron’s activity can actively and concurrently alter
the underlying biophysical state of both the synapse
and neural excitability. These changes can be viewed
as metaplastic in fashion, a form that when imple-
mented through a multiplicative operation resembles
a form of Hebbian-like metaplastic learning.
3. Results
The learning rule that we have developed is pre-
sented in the materials and methods section under
the subsection title neural-glial plasticity rule. The
timing-dependent plasticity and the impact of the
glial signaling on neural excitability and plasticity.
Our neural-glial plasticity rule simultaneously oper-
ates over two different timescales by combining tim-
ing dependent plastic change with slower alterations
of both the rule and the nature of excitability of the
neuron. Experiments have shown that neurons com-
municate with glial cells via glutamate that in turn
triggers changes in calcium signaling in the glial cell
in response to input.10, 12, 13, 47, 66, 71, 72 In a recipro-
cal manner, neurotransmitter is released from the
glial cell via an integrate-and-release process trig-
gered by calcium exceeding some threshold. Experi-
mental data has suggested that glial cell activity also
operates on a longer timescale by allowing changes
to both the learning rule at the synapse and the na-
ture of excitability of the neuron.6, 7, 12, 22, 47, 73 This
synapse-glial-neuron communication via calcium and
neurotransmitter forms the functional basis of our
tripartate synapse and leads to both activity driven
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0.5 0.08

0.07
20 0.4
0.06

Synaptic weights
Feature space

40 0.05
0.3
0.04
60 0.2 0.03

0.02
80 0.1
0.01

100 0 0
1000 2000 3000 4000 5000 0 20 40 60 80 100
Recording steps of 10 sec Feature space
(A) (B)
Figure 2. Here the standard STDP learning was applied to our network leading to a complete failure in the emergence
of input selectivity. Simulations started by setting the weights of connections from the excitatory input neurons to the
output neuron to the initial value of 0.5. In (A) we present how the synaptic weights from the excitatory input neuron
to the output neuron evolves over 50000 seconds, where 5000 snapshots of these synaptic weights are recorded every 10
seconds. (B) Illustrates the final synaptic weights after the learning process that lasted 50000 seconds. Clearly the output
neuron did not learn to respond selectively to an input feature.

metaplastic and excitability change. To demonstrate
the usefulness of our neural-glial plasticity rule, we
have used this new rule to illustrate that it can solve
the problem of input selectivity.
For this task, we have set up a network of spiking
neurons composed of an input layer consisting of 100
excitatory and 20 inhibitory cells, an output neuron,
and a single glial cell. The input neurons respond
in a stochastic fashion by action potential firing to
set of 10 input features. The neurons in the input
layer drive the output neuron to fire and the glial cell
to develop a calcium-based response signal, respec-
tively. Furthermore, the output neuron also provides
inputs to the glial cell, which in turn the calcium de-
rived activity of the glial cell generates a current in
the output neuron. The output neuron is described
by the Izhekevich model67 while the dynamics of the
glial cell is given by a system of ordinary differential
equations (ODEs). A full description of the network
architecture and the mathematical models for both
the output neuron and the glial cell are presented in
the material and methods section. The network was
stimulated by 10 input features by randomly select-
ing a pattern and presenting this to the network for a
total of 200 msec after which a new input feature was
randomly selected and used to stimulate the network.
A full description of the stimulus patterns and stim-
ulation paradigm is again described in the subsec-
tion entitled stimulation paradigm in the materials
and methods section. During stimulation, only the
synapses contributed by the excitatory input neu-
rons onto the output neuron are modified via learn-
ing. All other synaptic weights are fixed throughout
the simulation.
As an initial step standard STDP,45 using the
following parameters Ap = 0.0025, Am = 0.001125,
τp = 13.5 ms, and τm = 34.5 ms was applied to the
network to observe whether or not the output neu-
ron would learn to respond selectively to the input
patterns that were stimulating the system. Figure
2 shows the results of this initial simulation where
input selectivity failed to emerge using standard
STDP, noting that previous studies had required the
STDP rule to be modified according to the averaging
dynamics and mean rate of STDP learning to achieve
such a goal.
Figure 2 illustrates both the final set of synap-
tic weights and the evolution of these weights over
time. Figure 2(A) shows how these synaptic weights
change during the learning process that lasted 50000
seconds. Snap shots of these weights were recorded
every 10 seconds. Figure 2(B) illustrates the final
synaptic weights after the learning period of 50000
seconds. Clearly the output neuron did not learn to
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Figure 3. Here we present the neural-glial complex as a signal flow diagram that illustrates the interaction between the
learning rule, the neuron, and the glial cell as a tripartate partnership. Note how the learning process, neural, and glial
activities influence and interact with each other, where we note that this interaction takes place across two different tine
scales.

(A) (B)

Figure 4. Here the newly developed neural-glial plasticity rule was applied to our network and clearly leads to the suc-
cessful emergence of input selectivity. Simulations started by setting the weights of connections from the excitatory input
neurons to the output neuron to the initial value of 0.5. In (A) and (B) we present two different trials of how the excitatory
synaptic weights to the output neuron evolve over 20000 seconds, where 2000 snapshots of these synaptic weights are
recorded every 10 seconds. For both of these trials we see that the weight profile becomes tuned or well matched to one
of the input patterns after 20000 seconds of learning.

respond in a selective manner as the final weights
clear show no preference for a particular input fea-
ture. Clearly standard STDP has failed to generate
an output neuron that is selective for a particular
input feature. If it had been successful one would
have expected to see a final set of synaptic weights
that were both quite strong and well matched to a
single input feature. This matching of weights to in-
put feature guarantees the output neuron would fire
strongly and selectively for that input.
The neural-glial plasticity rule that we have de-
veloped possess two subtle yet important features.
Supported by experimental findings, the new rule
takes advantage of two different time scales where
plastic changes occur in the tripartate synapse of the
neuron-glial cell complex. The neural-glial plasticity
rule not only changes the synaptic weight of con-
nections but also adjust both the excitability of the
neuron and modifies the temporal aspects of plastic
change as learning progresses. In such a situation, the
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glial cell can be viewed as playing multiple rules in
addition to supporting the well-being of the neuron.
Here, glial cells actively take part in the learning pro-
cess, in a metaplastic fashion, and assists to adjust
learning and the operational level of neural circuits
over longer time scales probably in order to main-
tain neural activity relatively constant. We dub this
tripartate system the neural-glial complex where the
interaction between the neuron, glial cell, and the
influences of the learning process allows the plastic
change that occurs in the neural-glial complex to be
visualized from a signal flow point of view. Figure 3
presents the signal flow that occurs during learning
in the neural-glial complex.
We now repeat our experiment using the neural-
glial plasticity rule whose formulation is presented in
the materials and methods under the subsection ti-
tled neural-glial plasticity rule. This rule relies on
change synaptic weights using both timing informa-
tion and reciprocal signaling between the output neu-
ron and the glial cell. Figure 4(A)-(B) illustrates the
evolution of synaptic weights over a 20000 second
learning period. Two different trials are presented
where the neural-glial plasticity rule clearly leads to
the formation of an output neuron that can respond
selectively. Here it is evident that there is subset of
weights that are both strong and matched to one of
the ten inputs. This configuration guarantees that
the output neuron will fire both strongly and effec-
tively.
Figure 5. Here we show the final set of synaptic weights
that emerged as a result of applying our neural-glial
learning rule for a learning period of 20000 seconds.
Clearly the weights are well matched and overlap with
the fifth feature vector. Hence the output neuron is ex-
pected to respond vigorously and in a selective manner.
Figure 5 shows a single example of how the
evolved weights are a good match to one of the stim-
ulus inputs used during learning. For this example
the output neuron will respond robustly and selec-
tively to fifth feature input. Again the stimulation
paradigm is the same as that detailed in the materi-
als and methods section.
4. Discussion and Conclusion
Previous experimental and theoretical investigations
into synaptic plasticity have primarily focused on
understanding both the consequence(s) and mech-
anism(s) that give rise to synaptic change. Such
studies typically focus on the interaction between
pre- and post-synaptic neurons, the underlying phe-
nomenological or biophysical mechanisms, and the
resulting functional impact of this interaction both
at the single cell and network level.28–31, 36, 38, 41, 42
The participation of glial cells, however, is rarely
mentioned or discussed. Since the turn of the cen-
tury there has been a gradual change in consensus
on the roles played by glial cells where a proper and
thorough re-examination of their roles in both in-
formation processing and synaptic plasticity is re-
quired.2, 6, 17, 19, 20, 74 This is expected to generate a
clarification about the true roles played by glial cells,
such as astrocytes, during various cellular processes,
in particular their role during the development and
refinement of functional network activity and in-
formation processing. Re-examination of the roles
played by glial cells in the brain has largely been
triggered by novel experiments producing data that
has started to overturn traditional views and be-
liefs.6, 8–10 One of the more significant being that
glials are present simply to support the well being
of neurons and are not involved in neural transmis-
sion. This was considered the norm, however grow-
ing amounts of experimental data are now illustrat-
ing glial cell responses to inputs are driven by cal-
cium signals rather than voltage.24, 73, 75, 76 More-
over, experiments have shown that glial cells can
communicate with neurons by illustrating changes
in a neuron’s membrane potential in response to
glial cell activation have been recorded11, 14, 25, 66, 71
and phenomenologically quantified.60, 61, 77 Further-
more, experiments have also shown that astrocytes
can affect neural transmission6, 12, 46–48, 78 at the level
of single synapses and that glial cells can also in-
fluence synaptic plasticity.6, 7, 21, 22 Finally, there is
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growing evidence of their involvement in the reg-
ulation of cytokines79–82 and the development of
neurological disorders like epilepsy, depression, and
Alzheimer’s.46, 83, 84 Given that glial cells are esti-
mated to be ten times more numerous than neurons
and are responsible for around half of the mass of the
human brain,4, 5 it is now becoming critical that a far
more thorough and detailed re-examination of their
roles in brain function and information processing is
required.
In this paper we have studied how timing based
synaptic plasticity could be influenced by glial cell
activity during the development of input selectiv-
ity, based on the nature of the tripartate synapse.
Specifically, we presented a neural-glial learning rule
that integrates timing based synaptic plasticity with
the reciprocal nature of neural-glial communication.
This allows the rule to take advantage of dynam-
ics over two different timescales that allow neurons,
through their concerted interaction with glial cells, to
learn to respond selectively. Significantly, our study
is able to provide a biological foundation or sub-
strate to a commonly used augmentation that needs
to be used in spike timing based learning, such as
STDP. For STDP to promote the formation of input
selectivity requires introducing activity dependent
changes that augment the original rule, specifically
the maximal amplitude of the depression window is
altered in an activity dependent manner according to
the averaged long time dynamics of STDP learning.
This augmentation was introduced via a theoretical
construct. Our neural-glial rule however, is based on
properties of tripartate synapses and particularly on
reciprocal communication between the neuron and
glial cell, which allows the formation of input selec-
tivity. Changes in our learning rule result from meta-
plastic changes driven by correlation-based activity
between the neuron and the glial cell. This is im-
portant for two reasons. Firstly, it is known that the
glial cell can influence whether a synapse is potenti-
ated or depressed due to calcium-based neural-glial
signaling. Secondly, it hints at a potentially larger
role for glial cells in information processing specifi-
cally through their potential involvement in imple-
menting metaplasticity for both short-term and long
term changes. An interesting question about neural-
glial signaling is whether glial cells can act as a “Su-
pervisor” by providing some form of teaching signal,
or they can act more in a Reinforcement, or poten-
tially even in an actor-critic role. For this to be ex-
amined further, new experiments need to be devised
and carried out, in parallel, standard neural learn-
ing theory needs to be expanded to incorporate glial
cell activity and it is here that there could be an in-
teresting twist where neural-glial signaling may po-
tentially implement a correlation-based operation to
learning that is also viewed as implementing meta-
plastic change across two different timescales.
Significantly, this theoretical study was the first
display how neural-glial signaling can give rise to the
formation of a functional property called input se-
lectivity. We found that use of neural-glial signaling
and its physiology underlies metaplastic changes to
timing-based plasticity rules. Specifically, we found
neural-glial signaling to be critical in the neuron’s
ability to develop selective responses to a set of stim-
uli. Underlying this capability is the dual time scale
nature of signaling between neurons and glial cells
involving both glutamate neurotransmitter and cal-
cium based cellular signaling. This natural inclusion
of two temporal scales allows neural-glial plasticity to
simultaneously implement processes that give rise to
synaptic plasticity and metaplasticity. This is signif-
icant as it indicates that multiple time scales aid the
implementation of novel learning methods, including
yet to be discovered optimization strategies. Further-
more, from a theoretical view point, the inclusion
of multiple time scales via neural-glial signaling en-
riches the dynamical nature of learning, through the
involvement of various biochemical processes includ-
ing glutamate and calcium-based cellular signaling.
The dual time scale nature of neural-glial signaling
suggests that glial cells play an active role not only in
the maintenance but also in the formation and refine-
ment of functional properties of neurons and neural
circuits. Glial cells can also be considered to have a
somewhat elusive character in the sense that their re-
sponses are calcium-based rather than being voltage-
dependent. Finally, there is growing evidence to sug-
gest a novel hypothesis that glial cells may act as part
of a principal-agent neural framework as “gate keep-
ers” to neurons in the calcium domain controlling
the context and flow of information transfer between
neurons and influencing, and in some sense guiding
the formation and refinement of cortical circuits in a
asymmetric fashion. It is clear that the actual roles
of glial cells, despite being currently unknown, is ev-
idently far beyond their ill conceived and misleading
Pv3
10
portrayal as “passive” devices.
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