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com
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Synaptic plasticity in dendrites: complications and
coping strategies
Bartlett W Mel1, Jackie Schiller2 and Panayiota Poirazi3
The elaborate morphology, nonlinear membrane mechanisms
and spatiotemporally varying synaptic activation patterns of
dendrites complicate the expression, compartmentalization
and modulation of synaptic plasticity. To grapple with this
complexity, we start with the observation that neurons in
different brain areas face markedly different learning problems,
and dendrites of different neuron types contribute to the cell’s
input–output function in markedly different ways. By
committing to specific assumptions regarding a neuron’s
learning problem and its input–output function, specific
inferences can be drawn regarding the synaptic plasticity
mechanisms and outcomes that we ‘ought’ to expect for that
neuron. Exploiting this assumption-driven approach can help
both in interpreting existing experimental data and designing
future experiments aimed at understanding the brain’s myriad
learning processes.
Addresses
1 ing plasticity at a given dendritic location will be influ-
Biomedical Engineering Department and Neuroscience Graduate
Program, University of Southern California, Los Angeles, CA 90089,
United States
2
Department of Physiology, The Rappaport Faculty of Medicine and
Research Institute, Technion-Israel Institute of Technology, Haifa 35254,
Israel
3
Institute of Molecular Biology and Biotechnology (IMBB), Foundation
for Research and Technology-Hellas (FORTH), Heraklion, Crete, Greece
Corresponding authors: Mel, Bartlett W (mel@usc.edu),
Poirazi, Panayiota (poirazi@imbb.forth.gr)
Current Opinion in Neurobiology 2017, 43:177–186
This review comes from a themed issue on Neurobiology of learning
and plasticity
Edited by Leslie Griffith and Tim Vogels
For a complete overview see the Issue and the Editorial
Available online 25th April 2017
http://dx.doi.org/10.1016/j.conb.2017.03.012
0959-4388/ã 2017 Elsevier Ltd. All rights reserved.
Introduction
When Donald Hebb proposed his famous learning rule
[1], he referred to the very simple situation in which
neuron A participates repeatedly in the firing of neuron B,
leading to a stronger connection between them
(Figure 1a). Hebb’s rule may be the single most influen-
tial idea in the field of neural plasticity; it has affected the
thinking of generations of theorists and experimentalists
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by identifying both the variables and the interactions
between them that determine how the connection
between two neurons should change.
Most real neurons do not physically resemble Hebb’s
neurons A and B, however. Rather, they are dominated by
dendritic trees having a wide variety of shapes and sizes
[2–5]. Dendrites complicate the discussion of synaptic
plasticity since the number of variables that can influence
the direction and magnitude of changes at a given synapse
is radically increased compared to Hebb’s simple picture
[155]. Perhaps the simplest way dendrites complicate
neural plasticity occurs when different plasticity rules
apply to different dendritic subtrees (e.g. apical vs. basal)
within the same neuron [6

,7–11], or at a finer scale, to
different subregions within the same dendrite [12,13]
(Figure 1b). Dendrites introduce more profound compli-
cations when we consider that the voltage signals govern-
enced by a multitude of factors. First, local passive cable
properties of dendrites and spines can vary dramatically
across the dendritic arbor [14–22], influencing the size
and time course of the local voltage responses caused by
synaptic conductance changes. The voltage signals felt by
a synapse are also influenced by a multitude of excitatory
and inhibitory inputs activated elsewhere in the dendritic
arbor, whose combined effects at any given location
depend in complicated ways on distance travelled [23–
25], intervening dendritic diameters and branching struc-
ture [14,15,26,27], and boosting or suppression by volt-
age-dependent membrane mechanisms [28–33]—which
can themselves undergo activity-dependent changes that
modify dendritic excitability [6
,34–43]. Plasticity out-
comes can also depend on the relative timing of synaptic
inputs and back-propagating somatic action potentials
[8,9,44–47], whose penetration into the dendritic arbor
can be time, morphology and state-dependent [10,39,48–
51].
Synaptic plasticity can also be modulated by pathways
that target-specific subregions of a dendritic tree [52], or
even specific parts of a dendritic branch [13]. Inhibition,
for example, even if applied uniformly across a dendritic
tree, can implicitly promote compartmentalization of
plasticity by raising the threshold for plasticity induction,
so that only the most strongly activated dendritic com-
partments can participate in learning. This effect by itself
can lead to differentiation of the functions assigned to
different dendrites [53

,54

]. Dendrite-wide threshold
elevation likely does not fully capture the extent to which
inhibition can spatially restrict plasticity, however.
Current Opinion in Neurobiology 2017, 43:177–186
178 Neurobiology of learning and plasticity

Figure 1

(a) Hebb’s scenario (circa 1949)

A B
w

(b)
excitatory

inhibitory

firing

depolarized

silent

distal proximal

Current Opinion in Neurobiology

Synaptic plasticity within complex dendritic trees.

(a) The basic synaptic plasticity scenario suggested by Donald Hebb in 1949. The connection (w) between two neurons A and B increases if the
activity of neuron A repeatedly causes the firing of neuron B.
(b) Synaptic plasticity rules are potentially influenced in myriad ways by electrical and chemical signaling in dendritic trees. Pyramidal neurons, for
example, are organized into distinct anatomical compartments, including the apical tuft (yellow shading), the main apical tree (blue shading) and
the basal tree (green shading), within which synaptic plasticity rules can differ. Moreover, individual dendrites within these compartments can be
found in various activity states (e.g. silent, depolarized, firing) and these activity states along with synaptic input at both excitatory and inhibitory
synapses influence the production/diffusion of plasticity related molecules (green, yellow) that are necessary for synaptic plasticity. Finally, the
location of synaptic input, whether distal or proximal within a dendritic branch also influences synaptic plasticity as different rules may operate at
distinct locations within a branch.

Recent evidence suggests that interneurons can inhibit
certain dendrites within a neuron but not others [55–57],
can target-specific parts of specific classes of dendrites
(e.g. proximal parts of terminal basal dendrites [58
], or
can even target a restricted part of a single branch within
a neuron’s dendritic arbor [59]. This scale of wiring
specificity of inhibition is known from modeling studies
to have profound effects on dendritic integration
[23,24,33,60–62] adding to the list of mechanisms that
can influence synaptic plasticity outcomes at different
dendritic places and times within the same neuron.
Dendrites not only influence the communication of
voltage signals, but also chemical signals [63] that can
introduce distance and time dependence to local
plasticity rules, including Ras [64], Arc [65,66], numerous

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 Synaptic plasticity in dendrites: complications and coping strategies Mel, Schiller and Poirazi 179
plasticity-related proteins (PRPs) [67–70], as well as
mobilization and recruitment of receptors and channels
such as AMPA, Kv4.2, and HCN channels [71–75].
Finally, dendrites create the opportunity for ‘wiring plas-
ticity’, allowing a neuron to tap into huge capacity gains
[76–79], information binding [80], temporal linking of
memory engrams [81

], detection of temporally corre-
lated signals [82], and other benefits [83]. The elaborate
array of biological mechanisms controlling the formation,
stabilization and elimination of synaptic connections
between axons and dendrites must therefore be consid-
ered as an intrinsic part of the overall synaptic learning
scheme [84–89].
In summary, in comparison to Hebb’s classical A ! B
plasticity scenario, the mechanisms that collectively
determine when, where, how much, in what direction,
and with what effect plasticity occurs at a given site within
a dendritic tree are manifold, heterogeneous, and com-
plex, and we have far to go before reaching either a solid
or a comprehensive understanding of the impact of den-
drites on the plasticity of neural tissue.
The importance of learning problems and
readout mechanisms
A major thesis of this review is that, to help impose order
on the complex data field relating to local plasticity rules
in dendrites, we can exploit the tight relationship that
exists between:

the high-level learning (or developmental) problem
faced by a neuron,

the neuron’s input–output function, and

the plasticity rules whose job is to set the neuron’s
operating parameters.
In particular, knowledge gained about any of the three
can create useful expectations about the others. For
example, it would be surprising to discover in some brain
area an elaborate biological infrastructure that encourages
correlated groups of axons to seek out and form clusters of
synaptic contacts within the dendrites of their target
neurons if the target neurons’ input–output function
ignored such clustering. This is a case where knowing
that the plasticity rule creates clusters of inputs leads us to
expect that the neuron’s readout mechanism should be
sensitive to clusters of inputs. It would likewise be
surprising if a neuron was found to contain separately
thresholded dendritic subunits [18,31,39,90,91], and was
therefore highly sensitive to clustered patterns of synaptic
activation [31,76,92–95], but those functional subunits
played no role in solving the neuron’s high-level learning
problem [96,97,98

,99]. In this case, information about
the neuron’s readout mechanism creates expectations
about the high-level learning problem(s) that the neuron
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faces. In yet another example, knowing that a neuron is
involved in the storage of episodic memories, which by
definition occur only once, leads to the expectation that
any synaptic changes triggered by those experiences must
be essentially full and immediate [100,101].
Three learning scenarios
To explore these ideas further, we consider three cases
where a neuron finds itself in a different learning and/or
developmental scenario, and explore the requirements,
expectations, and counter-expectations regarding the
neuron’s dendritic readout mechanism(s) and plasticity
rules. Some of the inferences drawn are speculative, but
nonetheless illustrate the way assumptions about the
learning problem can powerfully influence our expecta-
tions as to how the neuron should operate, and how its
parameters should change during learning. Given this
review pays particular attention to the role dendrites play
in shaping plasticity rules and outcomes, as a reference
case we begin with a scenario where sophisticated den-
dritic processing is presumably not needed to learn or
perform the task (Scenario 1). We then move on to
consider two scenarios where subunitized dendritic com-
putation may be helpful or necessary, but differing in
other important respects, such as whether the learning
process primarily involves weight vs. wiring plasticity, and
whether synaptic changes are expected to be binary or
graded, among several other differences (see Table 1).
Scenario 1: A neuron that participates in a large number of
different sensory-motor tasks, where each task requires that the
cell learn a different, smooth, time-varying function that
depends on a vast number of input variables.
Consider a cerebellar Purkinje cell that controls a shoul-
der muscle or muscle synergy that participates in a diverse
set of sensory-guided tasks such as throwing, carrying,
chopping, digging, running, fighting, dressing, and a
multitude other tasks that cannot be anticipated – and
thus cannot be hardwired – by developmental processes
or evolution. The neuron must therefore be trained to
produce a multitude of different time-varying continuous
valued functions that encode each skill. In the course of
each behavior, the neuron’s firing rate depends differ-
ently on a vast number of somatosensory, proprioceptive,
vestibular, visual, motor efference copy, and contextual
inputs. Given the neuron’s input space contains so many
dimensions (presumably by design—see Refs. [102,103]),
the winding, often cyclic input-space trajectories tra-
versed by the neuron will scarcely overlap between tasks
[104]. As such, the learning problem faced by a neuron
can be caricatured as an ultra high-dimensional classifica-
tion problem in which the neuron learns to ‘recognize’,
through repeated training, a large number of randomly
scattered locations in a vast input space where its firing
rate must be elevated or depressed relative to baseline.
To the extent that this accurately describes the Purkinje
Current Opinion in Neurobiology 2017, 43:177–186
180 Neurobiology of learning and plasticity
Table 1
Three different learning/developmental problems and their plasticity characteristics
Sensory-motor skill
learning
Putative cell type/location Purkinje cell in cerebellum
Preferred size of learning unit Whole neuron
Primary plasticity mode Weight plasticity
Connectivity to dendritic tree Random
Subunit internal structure n/a
Synaptic weights Graded
Training Repeated
Supervisory signal Cell wide
role of LTP Learning in both cases
role of LTD
Synaptic meta states helpful? ? ‘age’
cell’s learning scenario, from an engineering perspective
the simplest design strategy is to construct a single-layer
‘Perceptron’4 [105] with modifiable synapses from all
potentially relevant inputs for all possible tasks combined
through a simple weighted sum [102,103,106,107,151,
152], see Figure 2a . [Given that a Purkinje cell receives
on the order of 250 000 synaptic contacts, its capacity to
‘label’ input patterns as described above is immense—on
the order of 250 000 [108,109]]. Following from this
model, we expect learning to be implemented by graded,
bidirectional, long-term-stable synaptic changes medi-
ated by conventional LTP and LTD processes [110],
and that the synaptic weight values will conform to a
predictable steady-state probability distribution [111].
Given that a Perceptron is essentially a linear device,
we do not expect to observe location-dependent nonlin-
ear interactions between parallel fiber inputs within
Purkinje cell dendrites, as they are not needed either
during learning or readout [151,152]. Furthermore,
given both the nature of the learning problem and the
highly constrained physical architecture of the parallel
fiber ! Purkinje cell interface, we do not expect to
uncover biological machinery that supports learning-
driven structural (wiring) plasticity between axons and
dendrites, as evidently occurs in other brain areas
[89,97,112,113].
This array of expectations and counter-expectations for
synaptic plasticity mechanisms on Purkinje cell dendrites
is collected in Table 1.
Scenario 2: A neuron that participates in an online, one-shot
familiarity-based recognition memory task.
4
The Perceptron is a device that can be trained to decide whether an
input pattern (e.g. set of activated synapses) belongs to one class or
another. It makes its predictions by combining a set of weights with the
input pattern through a dot product, and thresholding the result [105].
Current Opinion in Neurobiology 2017, 43:177–186
Online familiarity-based Development of a ‘complex cell’
recognition memory receptive field
Pyramidal cell in perirhinal cortex Pyramidal cell in early visual cortex
Dendritic subunit Dendritic subunit
Weight plasticity Wiring plasticity
Random Early: random
Late: structured
Flat Spatially sensitive
Binary Graded
One shot Repeated
None Early: somatic bAPs
Late: dendritic potentials
Learning To stabilize good connections
Forgetting To eliminate bad connections
?
(since last LTP event)
A memory of this type, sometimes called a ‘palimpsest’,
receives a continuous sequence of patterned inputs, and
must store a trace of each pattern based on a single
presentation, while causing as little disruption to previ-
ously stored memories as possible. Performance is
assessed by measuring the system’s ability to distinguish
familiar patterns from novel distractors as a function of the
time elapsed since the original presentation [114–120].
Familiarity-based recognition is thought to be centered in
the perirhinal cortex within the medial temporal lobe
[121,122]. Even when axons are wired to dendrites at
random (as in Scenario 1), the existence of separately
thresholded dendritic subunits, which are devoted to
recognizing partial patterns, has been shown to signifi-
cantly boost online storage capacity [120,123]. The
expectation in this scenario, therefore, is that the plastic-
ity rule should operate at the level of the individual
dendrite, and should involve both cooperative and
competitive interactions among nearby synapses in each
dendrite in which learning has been induced
[81

,85,87,124,125]. The act of storing a pattern should
involve one- shot LTP [12,101,120], whereas LTD
should be responsible for ‘forgetting’ at the end of the
memory’s lifetime [126,127]. Unlike the Perceptron
learning example in Scenario 1, in this old/new classifica-
tion problem we expect the steady state distribution of
synaptic weight values to be close to binary, that is,
consisting of only 2 categorically different long-term
stable weight values (strong and weak) [21,153,154],
though the absolute values of the weights might vary
according to the local dendritic input resistance
[12,17,18,21,128,129]. Finally, it was shown that a sub-
stantial capacity boost can be realized in this type of
memory if LTD mechanisms preferentially target
those synapses that have been least recently potentiated
(since they carry the oldest stored information); this leads
to the prediction that among the population of strong
synapses, the time elapsed since a synapse’s most recent
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 Synaptic plasticity in dendrites: complications and coping strategies Mel, Schiller and Poirazi 181

Figure 2

(a) Random connectivity Single layer "Perceptron"

x1
w1 weight plasticity
x2 w
2

Σ
in(t) out(t)
xk w
k

wo (t) = Q
xN w N

(b) Random connectivity 2-layer network with

conventional sigmoidal subunits

x1 w1
Σ weight plasticity
xk wk
.
.
Σ
out(t)
x1 w1
(t)
in(t)
Σ
xk wk

x1 w1
Σ
Strongly activated dendrite: xk wk
fires local spike
triggers local plasticity

(c) Structured connectivity 2-layer network with

spatially sensitive subunits

x1 w1
wiring plasticity
xk wk
.
.
Like-activated inputs x1 w1 Σ out(t)

form functional clusters in(t)

xk wk

x1 w1
Proximal-distal segregation
enables nonlinear xk wk
driver-modulator interactions

Current Opinion in Neurobiology

Schematics of 3 different learning scenarios.

(a) Scenario 1: a cell with random input connectivity is assumed to integrate its inputs linearly across the dendritic arbor, functioning as a single-
layer Perceptron. Image credit: NeuroMorpho.Org ID : NMO_10069

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182 Neurobiology of learning and plasticity
potentiation event – which could be weeks or months –
predicts its vulnerability to depression [118,120]. A can-
didate biological mechanism is the ubiquitin-proteosome
system, which seems well suited to manage synapse aging
through the elongation of ubiquitin chains, and has been
specifically suggested to orchestrate the dismantling of
synapses at the end of their lifetime [126,127,130–132].
Scenario 3: A neuron in the visual cortex that develops a
‘complex’ receptive field (RF) with multiple RF subunits, each
of which is modulated by subunit- specific contextual and/or
attentional inputs.
The receptive field (RF) of a “complex cell” (as defined
by Hubel and Wiesel [133]) typically contains two or more
oriented ‘simple cell’ subunits, each modeled as a thre-
sholded Gabor (or similar) filter [133–138]. Complex cells
exemplify the process whereby multiple similar ‘feature
detectors’ (speaking loosely) are pooled to create spatial
invariance—a process that is repeated through the multi-
ple stages of the ventral visual stream [139–141]. The
possibility that the multiple subunits of a complex cell RF
are mapped onto different dendrites has been discussed
in the literature [97,137,142,143], and though it remains
speculative, we explore here the constraints that the idea
imposes on the complex cell’s input–output function, as
well as the plasticity rules needed to set up the proper
wiring diagram (Figure 2c). One advantage of segregating
RF subunits onto different dendrites is that it permits
each subunit to be targeted by distinct modulatory inputs.
This is significant since it is known that both attentional
and contextual modulation of cells in early visual
cortex can act at a scale finer than the overall RF, that
is, can modulate one RF subunit separately from the
others [144–147]. Furthermore, both contextual and
attentional modulation effects are typically described
as ‘multiplicative’, in that they produce relatively little
effect on their own, but increase the gain of the cell’s
response to its classical driver inputs [144,148,149].
Subunit-specific gain boosting could be mediated by
nonlinear spatial summation effects in dendrites (see
Refs. [25,150] for a discussion of possible underlying
biophysical mechanisms). Establishing such a circuit dur-
ing development would require a wiring plasticity rule
operating both (1) at the dendrite scale, to sort the inputs
corresponding to different RF subunits onto different
dendrites, and (2) at the subdendrite scale, to sort classical
vs. modulatory inputs along the proximal distal axis of the
dendrite. In this scenario, we expect the plasticity pro-
cesses to operate mainly early in life; back propagating
(Figure 2 Legend Continued) (b) Scenario 2: a cell with random connectivity is shown with separately thresholded dendrites. In this case, the cell
acts as a conventional 2-layer neural network. When a dendrite receives strong excitation, a local spike is generated, and/or a local synaptic
plasticity event is triggered. Image credit: NeuroMorpho.Org ID : NMO_04127
(c) Scenario 3: a cell receives inputs that are spatially structured due to wiring plasticity. Structuring is schematized at two levels: (1) Correlated
inputs target the same dendrite (indicated by shared color scheme within each of three dendrites). (2) Within each dendrite, driver and modulator
inputs are shown spatially segregated. The dendritic nonlinearity (2-D mesh) in network shown at right represents within-dendrite nonlinear spatial
integration effects [150]. Image credit: Allen Institute
Current Opinion in Neurobiology 2017, 43:177–186
somatic action potentials (bAPs) to be instructive during
early development (during the establishment of the clas-
sical RF) but for local, dendritic potentials to regulate
plasticity later; and for LTP and LTD to act mainly as
arbiters of synapse survival or elimination during the
synapse spatial sorting process (Table 1).
Conclusions
Our starting point in this review has been that dendrites
add tremendous complexity and diversity to neuronal
plasticity mechanisms, relative to the simple scenario
envisioned by Donald Hebb (Figure 1a). Our main thesis
has been that when it is possible to know or make
reasonable guesses regarding the learning problem faced
by a particular neuron in a particular brain area, this
knowledge allows us to make surprisingly strong infer-
ences as to the role that dendrites may play in converting
the cell’s inputs to outputs, and the way that plasticity
rules should operate within the cell’s dendritic tree to
establish the proper wiring diagram, or to set proper
synaptic weights, or both (Table 1, Figure 2). One of
our main conclusions is that rather than expect stereo-
typed plasticity mechanisms, we should expect great
diversity in the way synaptic plasticity rules operate
within the dendrites of different neurons types within
different brain areas.
Conflict of interest statement
Nothing declared.
Acknowledgements
This work was supported by the European Research Council Starting Grant
dEMORY (GA 311435) to P.P.; the Israeli Science Foundation, the Adelis
foundation and the Prince foundation (J.S.).
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