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Review
Cite this article: Keck T et al. 2017
Integrating Hebbian and homeostatic plasticity:
the current state of the field and future
research directions. Phil. Trans. R. Soc. B 372:
20160158.
http://dx.doi.org/10.1098/rstb.2016.0158
Accepted: 20 October 2016
One contribution of 16 to a discussion meeting
issue ‘Integrating Hebbian and homeostatic
plasticity’.
Subject Areas:
neuroscience
Keywords:
Hebbian plasticity, homeostatic mechanisms,
theoretical modelling
Author for correspondence:Tara Kecke-mail: t.keck@ucl.ac.uk

Integrating Hebbian and homeostatic
plasticity: the current state of the field
and future research directions
Tara Keck1,†, Taro Toyoizumi2,†, Lu Chen3, Brent Doiron4, Daniel E. Feldman5,
Kevin Fox6, Wulfram Gerstner7, Philip G. Haydon8, Mark Hübener9,
Hey-Kyoung Lee10, John E. Lisman11, Tobias Rose9, Frank Sengpiel1,6,David Stellwagen12, Michael P. Stryker13, Gina G. Turrigiano11 andMark C. van Rossum14
1

Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
RIKEN Brain Science Institute, Wako, Japan3
Department of Neurosurgery, Stanford University, Stanford, CA, USA
4
Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA
5
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
6
Division of Neuroscience, University of Cardiff, Cardiff, Wales, UK
7
Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
8
Tufts University School of Medicine, Medford, MA, USA
9
Department of Cellular and Systems Neuroscience, Max Planck Institute of Neurobiology, Martinsried, Bayern,
Germany
10
The Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, USA
11
Department of Biology, Brandeis University, Waltham, MA, USA
12
Centre for Research in Neuroscience, McGill University, Montreal, Quebec, Canada
13
Sandler Neurosciences Center, University of California, San Francisco, CA, USA
14
School of Informatics, University of Edinburgh, Edinburgh, UK
2

TK, 0000-0001-6623-1037; TT, 0000-0001-5444-8829; DEF, 0000-0003-4646-8170;
H-KL, 0000-0002-5554-983X; JEL, 0000-0003-2676-225X; TR, 0000-0002-7156-4714;
FS, 0000-0002-7060-1851; DS, 0000-0003-3509-103X; MPS, 0000-0003-1546-5831;
MCvR, 0000-0001-6525-6814
We summarize here the results presented and subsequent discussion fromthe meeting on Integrating Hebbian and Homeostatic Plasticity at theRoyal Society in April 2016. We first outline the major themes and resultspresented at the meeting. We next provide a synopsis of the outstanding
questions that emerged from the discussion at the end of the meeting andfinally suggest potential directions of research that we believe are mostpromising to develop an understanding of how these two forms of plasticity
interact to facilitate functional changes in the brain.
This article is part of the themed issue ‘Integrating Hebbian andhomeostatic plasticity’.

1. Introduction†

These authors contributed equally to thisstudy.

Here we provide an overview of the topics presented at the meeting on Integrating Hebbian and Homeostatic Plasticity at the Royal Society in April 2016. Wealso summarize the major themes and questions that arose from the subsequentdiscussions. Firstly, one of the more pleasant and surprising take away messages from the meeting was the overall agreement between the conclusions
drawn from the data in numerous preparations, brain areas and approaches
to alter activity patterns and levels. We found that there are several generalprinciples that repeatedly emerge across approaches.
One of the more pleasant and surprising take away messages from themeeting was the overall agreement between the conclusions drawn from thedata in numerous preparations, brain areas and approaches to alter activity& 2017 The Author(s) Published by the Royal Society. All rights reserved.

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We review these general principles in turn, and then discuss important future directions to address inconsistencies
and missing points in our current understanding.

2. The necessity of stabilizing mechanisms
One question that is frequently raised outside of the homeostatic plasticity field is whether or not these stabilizing
mechanisms are actually necessary for proper brain function.
This question has been repeatedly addressed by theorists andmodellers, and their work typically indicates that withoutsome form of stabilization of firing rates or synaptic weights,
network models that can store memory patterns in recurrent
synaptic strength become unstable, typically in the directionof activity being too high [1–4]. These runaway increases
in activity emerge from the fact that most Hebbian strengthening mechanisms are dependent on coincident firing
between the pre- and post-synaptic neurons, and this process
involves a positive feedback loop: namely, the more frequentcoincident activity in a group of neurons is, the more likelythat synapses connecting these neurons are strengthened.
These strengthened synapses further increase coincident
activity within the group and very quickly, in a positive
feedback loop, activity pathologically increases.

3. Mechanisms of homeostatic stabilization
If some form of stability is necessary, what mechanisms may
provide this stability and what properties do these mechanisms have? Four major mechanisms were reported at thismeeting, although this list is not comprehensive of thepossible mechanisms, nor are they mutually exclusive.
(1) Synaptic scaling.
(2) Changes to inhibition through inhibitory cell activity or thestrength and number of inhibitory synapses onto excitatory
cells.
(3) Constraints and intrinsic fluctuations of spine size
dynamics (which likely reflect changes in synaptic
strength and thus overlap to some degree with stabilizing
mechanisms).
(4) A sliding threshold for long-term potentiation (LTP)
and long-term depression (LTD) induction (i.e. metaplasticity or the Bienenstock, Cooper and Munro(BCM) theory).

2

The first experimental evidence for synaptic scaling [5] demonstrated that in response to a decrease in firing rate, the synaptic
weights of the population of the excitatory post-synapses on acell were increasingly scaled in size by a multiplicative factor,
such that the relative weights of the synapses were preserved(and vice-versa in response to an increase in activity). Many
studies have confirmed this original result in vitro [6], as well
as ex vivo in acute slices prepared from both juvenile andadult animals that had previously undergone in vivo deprivation [7–14]. Synaptic scaling does have layer-specificproperties in cortex, where scaling in layer 4 is limited toearly development [7], but layer 5 [12,15] and layer 2/3 [10]can scale throughout adulthood. Numerous molecular mechanisms have been implicated in mediating synaptic scaling,including TNF-alpha [15–17], which may be regulated via
astrocytic activity and N-methyl-D-aspartate (NMDA) receptor
expression [18], retinoic acid [19], among many others (for areview, see [20,21]). Increases in TNF-alpha have been reported
to increase and decrease the density of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) and gamma aminobutyric acid-A (GABAA) receptors, respectively, in the plasma
membrane [17].

(b) Rapid changes to levels of inhibition
In addition to synaptic scaling, which takes several daysin vivo, altering the levels of inhibition and generally the balance between excitation and inhibition on a given cell is afrequently observed mechanism used to stabilize activity inthe brain. Reducing the levels of inhibition onto excitatoryneurons is consistently observed following loss of input in
cortex [10,22– 27] and has been hypothesized to be a firststep in circuit reorganization following input loss [28].
Changes in inhibition can occur via a reduction in thenumber [12,22,24,26,27,29–33] or strength of inhibitory
synapses onto excitatory cells [33], as well as a reduction in
the firing rate of the inhibitory neurons following deprivation
either temporarily during development [11,34] or for longer
time courses in adulthood [29]. Changes in inhibitory tone
may be modulated via astrocytes [35] or NMDA receptor
input [36]. Changing the activity of inhibitory neurons provides an important homeostatic mechanism by which
activity levels can be rapidly (within seconds) adjusted
through the increase or the decrease in the firing rate of inhibitory neurons to prevent short-term increases in activity levels
that would be associated with pathological activity such as seizures; however, recent work suggests that minimizing changes
to inhibition helps maintain temporal coding in the network,
which is shaped by the inhibitory circuit [37], so some maintenance of inhibitory tone is likely essential for the circuit.
Adjusting synaptic strength or neuronal excitability occurs
over much longer time courses of hours [6], which would
be much too slow to account for activity peaks that would
potentially cause pathological over-excitation.

(c) Changes and fluctuations in spine sizes
Dendritic spines—the location of excitatory synapses—canchange in size in response to long-term potentiation (LTP)
and long-term depression (LTD) [38,39] or while synaptic
scaling occurs [12,40], in a way that likely at least partiallyreflects changes in synaptic strength. Limits on the sizes ofPhil. Trans. R. Soc. B 372: 20160158(1) Stabilizing mechanisms are likely necessary to keep Hebbian changes to the system under control, otherwise
activity becomes extreme, either too high or too low.
(2) Multiple mechanisms of both Hebbian and homeostatic
plasticity are repeatedly observed across varied experimental and theoretical works.
(3) These mechanisms can stabilize numerous cellular andnetwork parameters—overall firing rate, subthreshold
activity and individual synaptic weights.
(4) Hebbian and homeostatic mechanisms have striking similarities observed among different brain regions in vivo
and in vitro, suggesting that many of these mechanisms
may be common across brain regions.

(a) Synaptic scaling

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patterns and levels. We found that there are several generalprinciples that repeatedly emerge across approaches.

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In order for these mechanisms to be truly homeostatic, they needto restore cellular and synaptic activity levels back closely to preperturbation levels. What characteristics of the circuit are beingstabilized by these mechanisms that make this process homeostatic? There is experimental evidence for three balanceparameters: firing rate homeostasis, subthreshold activity
homeostasis, and synaptic weight homeostasis, and any ofthese three parameters, when incorporated into the appropriate
theoretical model, may stabilize the network to prevent
pathological neuronal dynamics or learning [1,3,4,47–58].
First, firing rate homeostasis was initially describedwith the first experimental evidence of synaptic scaling [5],and altering cellular [59] and network firing rate has consistently evoked a response of the induction of homeostaticmechanisms [5,7,11,12,29,60]. Several studies have now
demonstrated that neurons will recover their firing rates
in vitro [5,59] and in vivo [11,12,29,60], in parallel with theinduction of homeostatic mechanisms, and that neurons in
the developing visual cortex have a firing rate set point towhich they return after deprivation [60]. Recent work has
also suggested that subthreshold changes in activity levels
are sufficient to induce homeostatic mechanisms, specificallysynaptic scaling [61], although whether these changes restore
subthreshold activity levels remains unexplored.
The sliding threshold proposed in the BCM theory would
provide an additional method by which firing rates could behomeostatically modulated [47]. By rapidly and superlinearly
increasing the threshold for inducing LTP as backgroundfiring rates get higher and decreasing the threshold as background firing rates are lower, synapses would be unlikely
to be strengthened if activity rates were too high. This sliding
threshold model would provide an internal mechanism bywhich activity levels never become too high or too low.
There is considerable experimental evidence for the existenceof such a sliding threshold, including both evidence of structural and functional plasticity, which has been reviewed
extensively elsewhere [62]. However, the timescale of the sliding threshold is an important factor for determining thestability [63], and the theoretically predicted supralinear
relation of the threshold with background firing rate isawaiting further experimental evidence.

5. Interactions with mechanisms of Hebbian
plasticity
Hebbian mechanisms have been largely reviewed elsewhere
and are well summarized in one of the position papers inthis issue [46]. An important feature of these Hebbian mechanisms in relation to their interaction with homeostaticmechanisms is that their time courses and effects can be
wildly different. Hebbian mechanisms are synapse specificand can be implemented over milliseconds (short-term plasticity) to hours (long-term LTP/LTD), whereas synaptic
scaling occurs cell-wide and can take a few days to commence in vivo [6,15,16,67]. Hence, there is a considerable
disparity between the effects and time courses between
these homeostatic and Hebbian mechanisms. Theoreticalwork suggests that separating the expression mechanisms(e.g. spine size or membrane AMPA density) for these twoprocesses can minimize their interface and prevent oscillatory
instability of synaptic weight, which could result from thedelay in the negative feedback of the homeostatic plasticity[53]. However, since multiple timescales are involved inboth Hebbian and homeostatic mechanisms, further experimental characterization of these disparate time courses isessential going forward [68].

6. Similarities across brain regions in vivo
For both Hebbian and homeostatic mechanisms, there are
striking similarities of plasticity responses across numerous
regions of cortex and varying plasticity induction paradigms(for a review, see [69]). Starting with homeostatic plasticity,
similar mechanisms are invoked following sensory deprivation in both somatosensory [15,26] and visual cortices[7,10 –15,22,24,27,60], where decreases in inhibition precedeany Hebbian mechanisms and synaptic scaling is reliably
induced in a layer-specific manner [7,26,70]. Hebbian mechanisms have correlates in synaptic structural plasticity, inwhich LTP is correlated with the formation of new spines[71,72], and LTD is associated with the loss of pre-existing
spines [73]. The in vivo upregulation of spine dynamics has
been observed following sensory deprivation in somatosensory cortex [74 –77], olfactory cortex [78,79], auditory cortex[80] and visual cortex [74,77,81 –83], and following learning
in motor cortex [84–86] where the memory of the learned
motor task depends on the newly formed synapses [87].
The interactions between Hebbian and homeostatic plasticity
have largely been described in the visual cortex following
monocular deprivation, where it is proposed that the Hebbian process of LTD [88] is followed by an increase insynapse strength [89]. The similarities across somatosensory,
motor and visual cortices may suggest that mechanisms of
homeostatic and Hebbian plasticity are conserved acrossbrain regions, at least in cortex.

3

Phil. Trans. R. Soc. B 372: 20160158

4. Parameters of homeostatic balance

Homeostasis of synaptic weights [64,65] provides an intriguing alternative to homeostatic regulation of firing rate, sinceconstraining synaptic weights would be an effective mechanism
for guiding activity-dependent circuit organization. Recent
work [66] suggests that overall synaptic weight is conserved
on a dendritic branch, thus preventing too much activity thatwould result from an over strengthening of synapses.

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dendritic spines provide yet another mechanism by which
stability can be achieved in the brain. Given that spine size
has a maximum [39], synapses cannot be strengthened indefinitely [41]. Furthermore, spine size is not only controlled by
LTP, LTD and during synaptic scaling, but also by intrinsic
fluctuations that happen even in the absence of neuralactivity [42]. Fluctuations of spine size increase approximately linearly with the initial size and this relationshipexplains the steady-state distribution of spine sizes with along tail [42,43]. A simulation study of recurrently connected
networks suggests that such fluctuations can stabilize network activity by constitutively restoring the spine size
distribution close to the physiological steady-state distribution, while ongoing Hebbian plasticity forms andmaintains cell assemblies [44,45]. In addition to changes inthe structural size of synapses, the properties and activationof NMDA receptors within a synapse have been implicatedin monitoring overall changes to activity levels [46].

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While a number of general experimental and theoreticalproperties emerged from this meeting, a large number of outstanding questions remain to be answered related to how
Hebbian and homeostatic plasticity interact to facilitate
normal function and circuit plasticity. Here, we outline themajor questions that were discussed at the meeting.

The field could generally benefit from tighter interactions
between theoreticians and experimentalists. One area forpotential expansion is in the interaction between theory andexperimental approaches that focus on detailed mechanistic
work, as well as more general behavioural/in vivo work.
Linking results at different levels of investigation, while ageneral issue in neuroscience, is particularly important tounderstanding the interaction between homeostatic andHebbian plasticity. Work in this field has to some degree
diverged into two categories. First, systems approaches that
include in vivo work done in anaesthetized or behaving animals [11,12,14–16,29,60,67] and theoretical work that models
the overall dynamics of the systems [1,3,4,47– 55,57,58,90].
These systems studies importantly provide insight into mechanisms that are used in the intact brain and how activity
levels are affected by these mechanisms, but have limited
control of other secondary inputs from outside of the main
pathways studied that may provide compensatory mechanisms. So these experiments often cannot pinpoint the exact
inputs and brain states affecting activity levels or the relativechanges to the pre- and post-synaptic cells, particularly
in behavioural experiments where the animals are free toexperience their environment (somewhat) naturally. Theselimitations make it difficult for the in vivo experiments to provide detailed information—for example, the originating brain
area from which inputs are lost following deprivation—tothese theoretical studies, where the localization of activity
changes ( pre- or post-synaptically) and knowledge of therules for circuit reorganization would be useful. As a result,predictions from theory to in vivo experiments and viceversa thus far are limited to qualitative aspects. The
second focus of experiments is at the molecular and cellularexperimental level, where numerous molecular mechanisms
have been described to play a role in both homeostatic[17,19,21] and Hebbian [91] plasticity, as well as their interactions [92,93]. While new molecular and systems tools
make it easier to link these molecular and cellular mechanisms to in vivo experiments, for example, through the use ofCre-dependent expression of target mechanisms, the brain’s
redundancy, evidenced by observed compensatory pathways,
can make it difficult at times to tease apart the precise roles ofindividual molecules in the healthy brain. Importantly, thetheory and molecular experiments may have greater potential
for interaction, which to date has been largely unexplored, as
theoretical models can predict the time course and spatial
scale of action of a molecular cue that would be necessary tofacilitate plasticity [94]. Given our knowledge of these potential
molecular cues in vivo and in vitro, this is one area where theoretical work could be instructive in linking the systems(b) Timescales of homeostatic and Hebbian plasticity
interactions
One of the important questions to emerge from this meeting is
how the disparate timescales of homeostatic and Hebbian plasticity could interact to maintain firing rate homeostasis andoverall stability. The main issue emerges from the fact that
homeostatic plasticity mechanisms occur over a very slow
time course, hours at their fastest [99], whereas Hebbian plasticity can occur over a period of seconds to minutes [46].
Given that recurrent excitation and synaptic strengthening
can happen very quickly, the stability mechanisms describedby the classic homeostatic mechanisms are not rapid enoughto stop runaway excitation. Theoretical models have described
approaches that facilitate network stability with these disparate
time courses [53], but at the same time suggested the need for afast downregulating homeostatic mechanism to avoid seizurelike activity [68]. One possible explanation for this discrepancy
between theory and experiment is that a majority of experiments focus on upregulating homeostatic mechanisms that
occur after input loss and a decrease in activity levels. Withthe upregulation of activity, a longer time course might be sensible, given that short-term deceases in activity levels could be
for a number of reasons—for example, in visual cortex, entering
a dark room could potentially reduce visual cortical activity. If
activity returns when you enter the light again, having quickly
upregulated the strengths of synapses in response to the dark
stimulus would result in too much activity with light stimulation. Hence, upregulating homeostatic mechanisms may
occur over a longer time course to ensure that the reduction ofactivity is (semi) permanent before the system compensates
for these changes. Additionally, using a wide dynamic rangeof activity is optimal for information coding in the brain [100].
Therefore, adjusting the firing rate set point too quickly
would minimize the range of activity patterns and rates that
encode input to a cell and in theory reduce its computational
power [53]. As a result, homeostatic adjustments may beslower when activity levels are not dangerous for toxicity.
These results could suggest the potential for a non-symmetric up- and downregulation, like that observed for LTP
and LTD, where potentiation can occur more reliably andquickly [46]. As for experimental evidence for homeostatic
downregulation, work in cortical cultures indicates that it ispossible [5,20], but approaches for extended increases in
activity in vivo remain elusive. The difficulty of maintaining
heightened activity in vivo for extended periods of time, may
speak to the existence of a fast downregulating homeostaticmechanism that has yet to be experimentally observed. The
relevant timescales for both homeostatic and Hebbian

4

Phil. Trans. R. Soc. B 372: 20160158(a) Interactions between theoretical and experimental
approaches

experiments with the molecular and cellular experiments. Similarly, mechanisms involved in the recovery of individual
neurons tuning following sensory deprivation in vivo
[11,12,14–16,29,60,67,95] could be explained via theoreticalwork. Theoretical models using attractor dynamics or hidden
states [96,97] could be implemented to better understand howinteractions between individual cells and the network of cells
facilitate the recovery of activity following deprivation andmaintain the same properties of individual cells from prior to
deprivation [95,98]. Overall, better interaction between molecular/cellular and systems level experiments and theory will be
critical to understand the underlying details of the mechanismsof plasticity and how they are implemented in vivo.

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7. Future directions and major questions going
forwardDownloaded from http://rstb.royalsocietypublishing.org/ on February 2, 2017plasticity mechanisms remain an unanswered question and acritical one for understanding their interactions.

(d) How do mechanisms interact?
Numerous homeostatic plasticity mechanisms (synaptic scaling, changes to the balance between excitation andinhibition, changes in excitability, spine size fluctuations;[99]) and Hebbian mechanisms (short-term plasticity, shortterm potentiation, LTP, LTD [46]) have been described. Thesemechanisms have largely been studied in isolation and there
is limited understanding of how these mechanisms may interact. For example, are multiple homeostatic mechanisms
engaged in an individual cell following input loss? If so, dothey all have the same threshold of activity change? Previous
work [13] indicates that different forms of deprivationinduce different homeostatic mechanisms in layer 2/3 of thevisual cortex ex vivo, suggesting that the exact nature ofPhil. Trans. R. Soc. B 372: 20160158

Similar to the issue of timescales, understanding the spatial
scales of both homeostatic and Hebbian mechanisms are critical for considering their interactions. Homeostaticmechanisms can be implemented at the level of individual
synapses [101], dendritic branches [66,102– 105], single cells[5,59] and the network [29], but obviously the interactions
between these spatial scales will play an important role inoverall firing rate homeostasis. For example, if the activity
at all individual synapses is homeostatically regulated, thenactivity in dendritic branches, single cells and the network
would be affected (and somewhat regulated) by that local regulation. The spatial scale of plasticity implementation is anotherarea where molecular and cellular experiments may match up
well with theory. Many of the more local implementations(individual synapses, dendritic branches and volume surrounding glial cells) of plasticity mechanisms may be
governed by second messengers and molecules acting inthese local environments. Thus, examining the relevant spatial
scales in theoretical models [106] may offer predictions for the
spatial and temporal characteristics of molecules that would
potentially facilitate some of the activity effects observed inthese models and in the in vivo data.
Understanding the spatial scales of the implementation ofplasticity mechanisms may also provide insight into thespatial scales for the set points of activity or synaptic
weight to which these homeostatic mechanisms are returning
the synapse, branch, cell or network. Whether homeostaticmechanisms are balancing spontaneous firing rate, evokedfiring rate, a combination of those two [60], the weight of
excitatory synapses [66] or subthreshold activity [61,107]
remains unclear. One possibility is that there may be multiple
spatial set points and the specific set point is regulated byhomeostatic mechanisms implemented at that spatial scale.
So balancing neuronal firing rates in the network would
occur via network level homeostatic mechanisms, and balancing synaptic weights in a dendrite would occur throughdendritic branch-level implementation of homeostatic mechanisms. How and when these different set points andhomeostatic mechanisms are implemented at these spatial
scales remain unanswered questions and are important forunderstanding how these plasticity mechanisms occur in vivo.

5

rstb.royalsocietypublishing.org(c) Spatial scales of synaptic plasticity and homeostatic
set points

changes in activity levels and patterns may influence how
and which homeostatic mechanisms are engaged. Additionally, if a cell does engage multiple mechanisms, the order ofengagement and further interactions between mechanisms
remains unresolved. Multiple studies suggest that the
reduction of inhibition levels occurs immediately after sensory
deprivation [11,23– 26,32], but the consequences for subsequent homeostatic or Hebbian mechanisms is not clear.
Consequently, it is an important future topic to explore how
individual mechanisms, as well as their interactions, affect behaviour. For example, at a mechanistic level, while TNF-alphaknockout mice show clear abnormalities in sensory responses[15,16], it is yet to be explored if this affects behaviours requiring sensory acuity. At a more general level, it is intriguing
to explore the interaction between different mechanisms,
as they can compensate for each other [108] and their
combination can achieve a non-trivial functional outcome.
In addition to the interactions among the homeostaticmechanisms themselves, the relationship between the Hebbian and homeostatic mechanisms is not particularly wellunderstood. Following monocular deprivation, circuit reorganization is proposed to occur via LTD [88], followed by
the homeostatic mechanism of either synaptic scaling [89] orchanging the sliding threshold to favour LTP [62], but whether
homeostatic mechanisms are only engaged after the cell has
induced Hebbian plasticity past some threshold (as may be
the case with monocular deprivation) or if these homeostaticmechanisms are constantly at work to never allow activity to
get too far out of range is unclear. One issue in the field isthat given the sensitivity of the currently used experimental
approaches, one needs to induce a strong change in activity
or a significant loss of input in order to be able to measurethat homeostatic mechanisms have been engaged. With theadvent of new, more sensitive tools to both manipulate
activity (light-activated channels) and measure activity (voltage-sensitive dyes), these questions will likely be resolved in
the near future. Finally, while numerous molecules havebeen identified to play a role in mechanisms of both types ofplasticity, there is an overlap between these molecular cues[93]. The interactions between the molecular mechanisms of
Hebbian and homeostatic plasticity are largely unexplored
and are an important question for identifying how thesedifferent types of plasticity are induced.
The study of homeostatic plasticity would also be greatly
advanced by the development of genetic and pharmacological methods for regulating and preventing it. Hebbian
plasticity can be controlled genetically by numerous
interventions, from manipulating NMDA receptors throughCaM-kinase-II-alpha to scaffolding mechanisms involved inreceptor trafficking, and pharmacologically by D,L-2-amino-5phosphonopentanoic acid (AP5) and 3-(2-carboxypiperazin4-yl)propyl-1-phosphonic acid (CPP). Experimental manipulation of homeostatic scaling has been achieved principallyby genetic or pharmacological alteration of TNF-alpha signalling; no selective manipulation is yet known for regulation of
inhibition. It will be important for advances in the molecularunderstanding of homeostatic plasticity mechanisms to leadto additional tools that can be used in vivo and targeted to
specific cells. Without such tools, it will be difficult to dissect
the interaction of these two forms of plasticity further andmake better connections with theoretical studies.
To conclude, the ideas that emerged at this meeting
reinforced many of the general concepts that have evolved

Downloaded from http://rstb.royalsocietypublishing.org/ on February 2, 2017of homeostatic and Hebbian plasticity, and whether the effector molecules are the same for these two forms of plasticity,(v) understanding the molecular mechanisms for three
types of homeostatic plasticity—synaptic scaling, modulationof inhibition and firing rate homeostasis, and (vi) understanding the temporal, spatial and mechanistic dynamics of
the understudied synaptic downscaling.

Authors’ contributions. All authors attended the meeting, participated inCompeting interests. We have no competing interests.
Funding. We received no funding for this study.

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the discussion and approved the final manuscript. T.K. and T.T.
wrote the manuscript.

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stability in the circuit can be maintained despite these differences in timescales, (ii) more effectively connecting theory
with molecular and systems level experiments, (iii) understanding the spatial scales of both the set points that thecells and networks are trying to achieve and the implementation of plasticity mechanisms, (iv) characterizing theinteractions, both spatial and temporal, between mechanisms

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