W.S. Sossin, J.-C. Lacaille, V.F. Castellucci & S. Belleville (Eds.)
Progress in Brain Research, Vol. 169
Copyright r 2008 Elsevier B.V. All rights reserved
Spine dynamics and synapse remodeling during LTP
and memory processes
M. De Roo, P. Klauser, P. Mendez Garcia, L. Poglia and D. Muller?
Department of Neuroscience, Centre Me ´dical Universitaire, 1211 Geneva 4, Switzerland
Abstract: While changes in the efficacy of synaptic transmission are believed to represent the physiological
bases of learning mechanisms, other recent studies have started to highlight the possibility that a structural
reorganization of synaptic networks could also be involved. Morphological changes of the shape or size of
dendritic spines or of the organization of postsynaptic densities have been described in several studies, as
well as the growth and formation following stimulation of new protrusions. Confocal in vivo imaging
experiments have further revealed that dendritic spines undergo a continuous turnover and replacement
process that may vary as a function of development, but can be markedly enhanced by sensory activation
or following brain damage. The implications of these new aspects of plasticity for learning and memory
mechanisms are discussed.
Keywords: dendritic spines; synaptic plasticity; structural remodeling; hippocampus; rat
A main approach to understanding learning and
memory mechanisms has been to examine how
information storage occurs at the level of a
synaptic network. The answer to this question is
now widely accepted to involve the contribution
of properties of synaptic plasticity and in parti-
cular, properties such as long-term potentiation
(LTP) and long-term depression (LTD; Bliss and
Collingridge, 1993; Cooke and Bliss, 2006). These
properties, through a lasting modification of the
efficacy of synaptic transmission, are believed to
durably alter the integration of synaptic responses
in target neurons and consequently their proba-
bility to fire in response to a specific input. This in
turn will re-shape the population of cells activated
by the input, providing therefore a mechanism
which, at the level of a neuronal network, fulfills
the criteria expected for a learning process. Indeed,
much evidence indicates that these properties of
plasticity are intimately associated to learning and
memory mechanisms (Cooke and Bliss, 2006).
LTP and LTD are induced by patterns of activity
that are physiologically relevant and enhanced
during learning in regions critical for memory
processes such as the hippocampus (Whitlock
et al., 2006). Also many examples of pharmacological
or genetic studies in rodents have shown correla-
tions between the capacity to express these proper-
ties and the performance in behavioral learning
tasks (Tang et al., 1999; Cui et al., 2004).
These results have thus strongly stimulated
research on the cellular and molecular mechanisms
?Corresponding author. Tel.: +41 22 379 5434;
Fax: +41 22 379 5452;
particular, the identification of the locus (pre- or
postsynaptic) and nature of the events responsible
for the lasting increase in synaptic efficacy has
represented an important issue and a continuous
subject of debate (Malinow and Malenka, 2002).
While the answer is likely to be complex, much
evidence indicates that modifications in the expres-
sion of postsynaptic glutamate receptors represent a
major mechanism accounting for the changes in
synaptic efficacy (Malinow and Malenka, 2002;
Nicoll, 2003). Currently, the most accepted view
proposes that NMDA receptor activation during
high-frequency stimulation leads to a rise in calcium
in dendritic spines which in turn activates signaling
cascades, among which protein kinases, such as
calcium/calmodulin dependent protein kinase II or
protein kinase C, are likely to play important roles
(Lisman et al., 2002). Through a sequence of
molecular events that are not yet fully understood
these signaling cascades probably affect the expres-
sion of specific subunits of AMPA receptors at the
synapse and thus the sensitivity to glutamate of the
postsynaptic structure (Malinow and Malenka,
2002). A main mechanism contributing to synaptic
enhancement thus probably involves a rapid
regulation of receptor expression at the synapse.
There are however also other mechanisms that
have been reported in association with synaptic
plasticity and in particular many studies have
examined the possibility that the structural organiza-
tion of the synapse or the number of synapses could
be modified (Yuste and Bonhoeffer, 2001). Spines
have indeed been shown to be dynamic structures
(Matus, 2000) that can be replaced at a rather high
rate in young animals and with some plasticity that
remains even in the adult. The possibility that
structural changes are associated with LTP or LTD
remains therefore an interesting and pertinent issue.
We review here some of the evidence supporting this
hypothesis and discuss these results in the context of
new data showing spine plasticity and turnover.
Morphological changes associated to synaptic
Ultrastructural analyses of spine synapses under
conditions of plasticity have revealed many changes
in the shape or size of spine synapses going from
enlargements of the spine head, formation of
protrusions, including spinules, or modifications
in the convexity or concavity of spines (Lee et al.,
1980; Fifkova and Anderson, 1981; Chang and
Greenough, 1984; Desmond and Levy, 1986;
Chang et al., 1991). However, a very frequent
finding that has been associated with changes in
synaptic activity or with plasticity is the occurrence
of perforated synapses, which on single sections
appear as synapses with a discontinuity in their
PSD (Calverley and Jones, 1990). Three-dimen-
sional reconstructions further show that the size of
increased and their shape may actually vary from
macular aspects to fully segmented PSDs with
separate release zones (Harris and Stevens, 1989;
Geinisman, 1993). Perforated synapses might thus
represent examples of highly functional synapses.
Changes in the proportion of perforated synapses
have been reported under multiple conditions: these
include (i) in vivo situations with animals stimu-
lated with LTP trains or following kindlings, or rats
raised in a complex environment, or submitted to
learning or training procedures (Greenough et al.,
1978), (ii) development or regeneration models in
association with synaptogenesis (Nieto-Sampedro
et al., 1982; Carlin and Siekevitz, 1983; Harris
et al., 1992) and (iii) in vitro situations following
LTP induction or epilepsy (Geinisman et al., 1993;
Buchs and Muller, 1996; Stewart et al., 2005).
Overall the formation of perforated synapses is
likely to be related to changes in synaptic functions,
although many aspects of their properties remain
unclear. It is still unknown what is the dynamic of
perforated synapses, how long they maintain their
organization, are they only transient as suggested
by some in vitro studies (Toni et al., 1999), what are
the release properties and the level of synaptic
efficacy expressed at perforated synapses? Answers
to these questions will be required in order to better
understand their role in plasticity.
In addition to perforated synapses, a few other
morphological changes have also been described.
These include spines with multiple synapses,
multisynapse boutons in which the presynaptic
terminals contacts several spines and bifurcating
spines found in association with an increase in
spine density (Trommald et al., 1996; Collin et al.,
1997; Toni et al., 1999, 2001). These changes have
been reported both under in vitro situations
following LTP induction or short ischemic condi-
tions, and also under in vivo situations following
learning or training protocols. Overall these
changes have generally been suggested to reflect
Morphological remodeling of activated spines
Most of the morphological changes reported
above under plasticity conditions were in fact
observed following large-scale analyses of synapses
using EM approaches. A major drawback of this
type of approach is related to the impossibility to
really appreciate how exactly they were related to
activity, whether they concerned mainly or exclu-
sively activated synapses and what was their
evolution over time. Only a few studies developed
approaches to try to address this issue. In previous
work in hippocampal slice culture, we used a
calcium precipitation methodology to try to
identify activated synapses and then determine
their morphology over the next 2h using EM and
3D reconstruction. While this technique clearly
allowed to detect a population of spines with
calcium precipitate, it was not fully devoid of
biases, since there was some level of background
staining, and furthermore precipitate often tended
to be localized in the spine apparatus and thus in
larger spines. However, despite these caveats, the
approach revealed several interesting findings. In
particular, activated spines observed 30min after
stimulation were characterized by larger spine
heads and larger PSDs and exhibited a greater
proportion of perforated synapses (Buchs and
Muller, 1996). Interestingly however these changes
were not stable and found to reverse to control
values after 2h (Toni et al., 1999). They were thus
interpreted as suggesting a fast remodeling of
synaptic membranes with extension of the receptor
zone, the whole process being detectable for about
30–60min following LTP induction.
The recent development
2-photon imaging applied to in vitro preparations
has made it possible to further investigate the
behavior of activated spine synapses following
activity or LTP induction. Calcium transient in
spines were reported to affect their morphology
(Korkotian and Segal, 2001) and recent work by
Matsuzaki et al. (2004) showed that induction of
LTP through release of caged glutamate was
associated with a lasting increase in the size of the
spine head, an observation also made following
chemical induction of LTP (Kopec et al., 2006).
Other studies however failed to observe such
changes, at least on a short time scale (Bagal
et al., 2005), and Lang et al. (2004) only found a
transient expansion of stimulated spines. In con-
trast, EM studies have regularly strengthened the
good correlation existing between spine head size,
PSD size and level of receptor expression (Harris
et al., 1992; Nusser et al., 1998). Thus, although
many data point to an increase in size of dendritic
spines and of their PSD following LTP induction,
further work will be required to determine whether
these changes accompany or, on the other hand,
are necessary for the expression of the potentia-
tion. New approaches combining confocal and 3D
EM studies might provide new means to address
Synaptogenesis associated to plasticity
A second very interesting morphological correlate
of LTP mechanisms is the possibility that plasticity
also involves the growth of new protrusions and
formation of new synapses. Work by several
laboratories provided evidence for such a process
in association with LTP stimulation (Engert and
Bonhoeffer, 1999; Maletic-Savatic et al., 1999;
Toni et al., 1999). Such changes were mainly
reported under in vitro conditions, but also
following sensory stimulation in the cortex of
adult animals (Trachtenberg et al., 2002; Holtmaat
et al., 2006). Under these conditions, new spines
can be formed de novo within periods of 30–60
min following stimulation and 3D EM studies
suggest that some of them at least may indeed
become mature synaptic contacts (Toni et al.,
1999). Quantitatively, the phenomenon is clearly
significant since up to 1–2% of new protrusions
have been reported within 2–3h following LTP
induction protocols. Interestingly also, while new
protrusions can be formed following LTP induc-
tion, the reverse appears to occur following
application of LTD protocols (Nagerl et al.,
2004). Thus protrusion growth and spine elimina-
tion are two opposite facets accompanying bidire-
ctional plasticity of excitatory transmission.
An important issue with regard to these activity-
dependent mechanisms of spine formation is
whether they ultimately result in the formation of
stable, functional synapses and whether this
process does contribute to the synaptic enhance-
ment characterizing LTP. The first new spines
formed upon LTP induction or other stimulation
protocols have mainly been reported 20–30min
after stimulation and their number appeared to
then progressively increase over the next few hours
(Jourdain et al., 2003; Engert and Bonhoeffer,
1999). This result thus clearly indicates that new
protrusions cannot directly account for the synap-
tic potentiation that is detectable as early as a few
minutes after stimulation. This does not exclude
however that new spines formed after LTP
induction could contribute at later time points to
the enhancement of synaptic responses. For this,
newly formed spines should become functional
synapses and involve similar presynaptic axons as
the ones activated during high-frequency stimula-
tion. Our previous 3D EM analysis of stimulated
synapses suggested that this could indeed happen
at least in some particular cases, since we found
examples of duplicated spine synapses, 2h after
LTP induction, where two spines from the same
dendrite contacted the same presynaptic partner
(Toni et al., 1999). This situation is however not
likely to be the rule for two main reasons. In a
recent study of spine turnover, we found that
a great proportion of newly formed spines are in
fact likely to disappear rather quickly, and that
their stabilization requires expression of a PSD
which usually becomes detectable on new spines
only between 5 and 19h after formation of the
protrusion (De Roo et al., 2008). This was also
confirmed in a recent study (Nagerl et al., 2007)
that reveals that the formation of morphologically
functional synapses, as analyzed by 3D EM
reconstruction of newly formed spines after LTP
induction, is a process that takes time. New spines
only a few hours old only rarely formed synapses,
while they more consistently expressed features of
functional synapses after 15–19h. This is also in line
with previous in vivo data that indicated that a few
days were required for the formation of morpholo-
gically mature synapses (Knott et al., 2006). Thus all
together, these studies strongly suggest that, while
synaptogenesis is likely to take place after LTP
induction and result in the formation of mature
synapses, these synapses are unlikely to account for
the synaptic enhancement associated with LTP or at
least not within the first hours or days.
Mechanisms of plasticity-induced synaptogenesis
If synaptogenesis and synaptic enhancement are
two separate mechanisms induced by the same
patterns of activity, an important issue then is to
understand how they are regulated. Experiments
show that both of them require NMDA receptor
activation and depend on calcium influx in the
postsynaptic cell. A further link between protru-
sion growthand potentiation
concerns the molecular events contributing their
regulation. In particular, protein kinases, such as
PKC, and also CaMKII, which play a critical role
for the functional changes in synaptic strength,
appear to regulate protrusion formation (Jourdain
et al., 2003; Pilpel and Segal, 2004). It is therefore
likely that the same mechanisms that control
expression of receptors might also sub-serve
changes in protrusion numbers. The downstream
effectors of these changes remain however yet
Another interesting question is whether these
new protrusions grow in an undefined manner or
whether their growth is more directed towards, for
example, pre-existing and possibly activated bou-
tons. An interesting morphological feature which
might bring an answer to these questions is the
frequent observation under conditions of synapto-
genesis of multiple synapse boutons where several
spines contact the same terminal. Special cases of
multiple synapse boutons in which two spines
arising from the same dendrite and contacting the
same terminal were found following LTP induction
in hippocampal slice cultures (Toni et al., 1999).
Another study has further shown an increase in
multiple synapse boutons under in vivo conditions
following learning protocols (Geinisman et al.,
2001). Finally, studies of spine dynamics in the
somatosensory cortex showed that spines initially
grow without a synaptic contact and then get in
touch with a presynaptic partner which, in many
cases, already formed a synapse with another spine
(Knott et al., 2006; Toni et al., 2007). This was
also the case of the new spines reconstructed after
LTP induction (Nagerl et al., 2007). This therefore
clearly suggest a directed mechanism where new
protrusions probably grow towards existing boutons
and there get in competition with the synapses
already established by other spines. Accordingly,
by stimulating spine growth, LTP mechanisms
might in fact promote competition between spines
and a process of input selection which might be
reflected by the observation of multiple synapse
Spine turnover and synapse formation mechanisms
An important new aspect of the mechanisms of
spine dynamics was brought by experiments of
repetitive confocal imaging in living mice. Studies
by several groups provided evidence that dendritic
spines do undergo some sort of turnover and that
there exist a process of continuous growth and
elimination of spines (Grutzendler et al., 2002;
Trachtenberg et al., 2002). Although there has
been some debate about the magnitude of this
phenomenon, an issue that may be related to the
approach used for imaging live neurons (Xu et al.,
2007), current evidence indicates that spine turn-
over varies greatly during development, affecting
as many as 10–15% of spines per 24h in very
young animals. Later on spines become progres-
sively more and more stable with only less than a
few percent of spines undergoing replacement in
adult tissue (Zuo et al., 2005). Furthermore this
process appears to vary in different cortical regions
and even show some cell-type specificity (Holtmaat
et al., 2005). Finally some data suggest that this
spine turnover process could also be affected by
sensory activity and thus promote remodeling of
synaptic networks (Holtmaat et al., 2006).
This phenomenon of spine turnover is particu-
larly important in young hippocampal slices
cultures, a model that is very often used for
studying plasticity and learning-related mecha-
nisms. Through repetitive imaging of the same cells
over several days in hippocampal slice cultures, we
recently found that the rate of spine turnover
affects about 20% of all spines in 15-days-old
cultures, but only about 10% after 25 days in vitro
(De Roo et al., 2008). These values, which are
quite close to those obtained in very young
animals, suggest that spine turnover retains similar
properties in vitro than in vivo and particularly
its developmental dependency. Another interesting
aspect was that this rate of spine turnover is
actually underestimated by the use of long
observation intervals. It turns out that in 15
DIV slice cultures, the basal rate of protrusion
formation reaches values in the order of 2% of
all spines per hour, which represents hundreds
of new protrusions per day and per neuron. The
reason why spine density remains nevertheless
stable is that most of these new protrusions do
in fact disappear fairly quickly and only a
small proportion of them become stable spine
synapses (Fig. 1). Curiously, we found, in agree-
ment with other in vivo studies, that filopodia,
usually considered as precursors of spine synapses,
only exceptionally lead to formation of stable
contacts (Zuo et al., 2005). Protrusions are thus
generated at a high rate, but only a fraction of
them become finally stable spines. We also found
that this required a process of maturation that
lasted about 24h. During this period, new spines
usually grew in size and started to express a
PSD after about 5h (Fig. 1) (Knott et al., 2006;
De Roo et al., 2008). Interestingly, expression of
this PSD was activity-dependent, since blockade
of AMPA and NMDA receptors prevented its
expression and reduced the probability of the spine
to be stabilized. All together these experiment
suggested a model in which development of
synaptic networks proceed through an extensive,
non specific growth of dendritic protrusions,
followed by the stabilization of a small number
of spines. This appears to involve the expression of
a PSD through mechanisms that are driven by
Memory and synapse formation mechanisms
The interesting implication of these new data is
that in young cortical structures, development
of synaptic contacts on a given neuron occurs
through a mechanism of trial and error where
most of generated protrusions are in fact rapidly
eliminated. In this process a factor that seems to
be important to stabilize new protrusions is the
presence of an active terminal in the vicinity. The
glutamate so released could drive the expression
of a PSD on the new spine and thus promote its
stabilization. Overall, these experiments also point
to the rather low level of stability and high rate of
with 100 PSDs (%)
Spine age (hours)
per 24h (%)
Filopodia fate (%)
New mushroom fate (%)
D1 D2 D3D4
Fig. 1. Spine dynamics in hippocampal organotypic slice cultures. (A) EGFP transfected CA1 pyramidal neuron. (B) Repetitive
imaging of a dendritic segment at 24h interval reveals the occurrence of new and lost protrusions. (C) Summary of the proportion of
stable spines (open column), which include spines exhibiting changes in morphology (dashed column), of newly formed (black column)
and disappearing (gray column) spines. (D) Stability over 5 days of newly formed filopodia. Note that most of them disappear within
1–2 days and only exceptionally lead to the formation of a stable spine. (E) Stability of newly formed spines. (F) Illustration of a newly
formed spine (ageo5h; arrow head, middle panel) which do not express PSD-95-DsRed2 (arrow head, lower panel). (G) Time course
of PSD-95-DsRed2 expression in newly formed spines. (See Color Plate 11.1 in color plate section.)
replacement of dendritic spines in young tissue.
This clearly raises issues with regard to mecha-
nisms of learning and memory under such situations
and emphasizes the likely importance of synapse
remodeling for these processes. Indeed in pre-
liminary work, we found that an important effect
of LTP induction in slice cultures is to enhance the
basal rate of protrusion formation over a period of
several days, leading to an increased and lasting
competition between spines. These observations
thus clearly point to the role of spine pruning and
replacement as a major mechanism susceptible to
affect the organization of synaptic networks
during development. LTP in this context might
have an important function by promoting and
enhancing the phenomenon. Theoretical work
does indeed suggest that spine remodeling could
represent an extremely powerful mechanism for
processing and storing information (Mel, 2002;
Chklovskii et al., 2004).
Thus, while Hebbian mechanisms affecting
synaptic efficacy certainly represent a powerful
tool for quickly modifying signal integration in a
given network, it is not unlikely that the long-term
maintenance of memory traces could also depend
on network reorganization mechanisms associated
to synaptic plasticity (Feldman and Brecht, 2005).
In this sense, changes in synaptic function and
remodeling of the network could represent two
different, but inter-related aspects of the mecha-
nisms underlying learning and memory formation.
Since the discovery that LTP induction in hippo-
campus not only affects synaptic efficacy but also
promotes growth of new protrusions, evidence has
continued to accumulate indicating that spines are
indeed dynamic structures that may undergo
continuous replacement throughout life. Although
it appears that these dynamic properties are mainly
expressed in young developing cortex, a capacity
for structural plasticity is clearly retained in adult
animals (Grutzendler et al., 2002; Trachtenberg
et al., 2002; Holtmaat et al., 2005; Majewska et al.,
2006). Although only a few percent of total spines
seem to be regularly replaced in older tissue, this
still represents a significant capacity for reorgani-
zation of synaptic networks. Furthermore these
properties might be reactivated under specific
circumstances where plasticity is required, for
example, following ischemic damage or neurode-
generative diseases (Grutzendler and Gan, 2006).
Accordingly the capacity of LTP to promote spine
growth and synapse remodeling during several
days following stimulation might in fact reveal a
key mechanism for the acquisition and then long-
term maintenance of new information, providing a
new mechanistic link between forms of neuronal
activity and the development and plasticity of
synaptic circuits. Thus in addition to the Hebbian
concept of changes in synaptic strength, it becomes
more and more apparent that activity-dependent
another major aspect of the changes induced by
specific patterns of neuronal activity.
This work was supported by the Swiss Science
Foundation and the European project Promemoria.
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