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Available online at www.sciencedirect.com
Structural plasticity of dendritic spines
Miquel Bosch1 and Yasunori Hayashi2
Dendritic spines are small mushroom-like protrusions arising
from neurons where most excitatory synapses reside. Their
peculiar shape suggests that spines can serve as an
autonomous postsynaptic compartment that isolates chemical
and electrical signaling. How neuronal activity modifies the
morphology of the spine and how these modifications affect
synaptic transmission and plasticity are intriguing issues.
Indeed, the induction of long-term potentiation (LTP) or
depression (LTD) is associated with the enlargement or
shrinkage of the spine, respectively. This structural plasticity is
mainly controlled by actin filaments, the principal cytoskeletal
component of the spine. Here we review the pioneering
microscopic studies examining the structural plasticity of
spines and propose how changes in actin treadmilling might
regulate spine morphology.
Addresses
1
The Picower Institute for Learning and Memory, Department of Brain
and Cognitive Sciences, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA
2
Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan
transduction molecules, ion channels, and cytoskeletal
components [7]. In addition to the PSD, the spine membrane may contain specialized microdomains for endocytosis or exocytosis [8,9]. The cytoskeleton in spines is
mainly formed by actin filaments (F-actin), which serve
both as a structural framework and as the principal regulator of protein and vesicular trafficking [10–12]. Mature
spines may also contain intracellular membranous structures (e.g. spine apparatus or amorphous vesicular
clumps), protein synthesis machinery such as polyribosomes, and mitochondria [13–17]. The spine head is
connected to the dendritic shaft via a thin neck (width
of 0.2 mm) that is thought to work as a diffusion barrier
for molecules and ions. Moreover, the spine and the
presynaptic terminus are surrounded by perisynaptic glial
processes, thereby forming a tripartite synapse [18,19].
These morphological characteristics have led researchers
to consider that the dendritic spine may function as a
microcompartment that confines postsynaptic signaling
both chemically and electrically [1,2,20,21].
Corresponding author: Hayashi, Yasunori (yhayashi@brain.riken.jp)
Current Opinion in Neurobiology 2011, 22:1–6
This review comes from a themed issue on
Synaptic Structure and Function
Edited by Morgan Sheng and Antoine Triller
0959-4388/$ – see front matter
# 2011 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2011.09.002
Morphology of the dendritic spine
In the vertebrate central nervous system, excitatory
synapses are usually formed on small, mushroom-like
protrusions on dendrites called dendritic spines [1,2].
Typically, one single glutamatergic synapse is formed
at the head of a spine, although some spines may receive
multiple presynaptic termini or non-excitatory inputs
[1,3]. Spines are composed of highly specialized subdomains exerting different functions in synaptic transmission and plasticity. Beneath the synapse, one can
find an electron-dense disc-like structure, called the
postsynaptic density (PSD). The PSD is composed of
multiple proteins that bind with each other through
specific domain–domain interactions, forming a meshlike structure organized in consecutive layers [4–7].
These proteins include neurotransmitter receptors, scaffolding proteins that stabilize those receptors, signal
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Spines exhibit a wide range of size and shapes, even
within a single neuron. During cortical development,
spines are rather thin and elongated and gradually gain
a typical mushroom-like structure with a prominent head
and a thin neck as the tissue matures [22–24]. There is a
positive correlation between the spine head volume, the
PSD area, the presynaptic active zone area, the number of
AMPA-type glutamate receptors, and the synaptic
strength [25–27,28]. These correlations suggest that
spine structure is tightly coupled to synaptic function.
Furthermore, time-lapse studies have shown that spines
are extremely plastic and motile. In sensory cortex, this
motility is regulated by sensory experience and significantly decreases with age [22,29,30]. However, we still do
not fully understand the intrinsic relationship between
structural and functional plasticities of the spine. Therefore, it is of great interest to know how spine head and
neck morphologies are regulated by neuronal activity to
ultimately comprehend why spines have such unique
shape and how its modifications affect synaptic functions.
Electron microscopic studies on the activitydependent structural plasticity of dendritic
spines
The very first evidence supporting the structural modification of dendritic spines associated with synaptic
activity came from a series of electron microscopic
(EM) studies by Eva Fifková and co-workers in 1970s
to 1980s. They induced long-term potentiation (LTP) at
synapses between hippocampal perforant path and dentate granule cells in vivo, using the same preparation
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2 Synaptic Structure and Function
wherein Bliss and Lømo [31] reported the first synaptic
plasticity in the mammalian central nervous system. Only
two years after the study by Bliss and Lømo, Fifková and
co-workers found that dendritic spines on stimulated
pathway were larger than those in unstimulated pathway
or in control animals [32]. This enlargement was found
as early as 2 min after tetanic stimulation and lasted up to
23 h [33]. At the same time, they found wider and shorter
spine necks after LTP induction [34]. If we approximate
the spine neck to a cylinder, we calculate that these
changes reduce the spine electrical resistance by 74%
at 4 min and by 54% at 60 min. These changes may lead
to more efficient transmission of electrical current generated at the dendritic spine head.
Using a similar approach, Desmond and Levy observed an
increase in the proportion of concave-shaped spines with a
concomitant decrease in those with simple and ellipsoid
shape [35]. Along with it, total PSD surface area associated
with concave spines increased significantly [36]. Harris and
co-workers examined CA1 pyramidal cells in hippocampal
slices, a conventional preparation for studying LTP, with
electron microscopy and found that the percentage of
spines containing polyribosomes increased 2 h after a
tetanic stimulation [15]. Those spines contained significantly wider PSD as well. Other features commonly found
after LTP induction is an increase in the number of spines
with perforated PSD [23,37,38], the number of bifurcated
spines ([39], but also see [40]) and the formation of spinules
from the spine head [41,42]. These studies strongly support the view that the structure and contents of a dendritic
spine can undergo long-term modifications during synaptic
plasticity.
Light microscopic studies on the activitydependent structural plasticity of dendritic
spines
In these EM studies, because of an obvious lack of capability of time-lapse imaging, it was not possible to demonstrate whether existing spines became enlarged or whether
spines with larger size were generated de novo by LTP
induction. It was even not possible to know whether a
given synapse under observation was actually potentiated
or not. Those results relied on statistical differences between different populations of spines and, therefore, had a
certain limitation in interpretation as to whether they were
truly observing phenomena directly associated with LTP
or processes occurring in parallel and not directly involved
in the induction or maintenance of LTP itself.
Hosokawa et al. were the first to attempt time-lapse
imaging of the same set of dendritic spines in hippocampal slices before and after LTP induction [43]. They
used a confocal microscope to observe DiI-labeled
neurons and found an increase in length in a subpopulation of small spines 3 h after the induction of chemical
LTP. Maletic-Savatic et al. employed two-photon
microscopy in GFP-transfected neurons and induced
LTP by local stimulation with a glass electrode [44].
They observed the generation of new filopodia-like protrusions and, at the same time, the loss of existing spines.
Engert and Bonhoeffer [45] also carried out a similar
experiment by locally perfusing a dendritic segment with
Ca2+-containing extracellular fluid while suppressing
synaptic transmission in the rest of the dendrite by
Cd2+-containing solution. Electrical stimulation resulted
in the generation of new spines only in the segment
where Ca2+ was available. However, the generation of
new spines did not synchronously occur with the increase
in the synaptic transmission. While the increase in excitatory postsynaptic current (EPSC) amplitude was
observed within a few minutes after LTP induction,
the generation of new spines occurred much later.
Therefore, it still remained an unanswered question
whether the enlarged spines indeed underwent LTP or
not. To elucidate this issue, Matsuzaki et al. [28,46]
employed a two-photon-induced glutamate uncaging
technique, which allows the controlled release of glutamate in a very small volume compared with other
approaches (such as local glutamate application through
pipette or conventional UV-mediated uncaging method).
Combined with electrophysiological recordings, they
showed that repeated uncaging of glutamate in Mg2+-free
solution induced both an expansion of the dendritic spine
as well as an increase in the synaptic electrical response.
Okamoto et al. [47] found a similar expansion of the
dendritic spine that synchronized with the local electrical
stimulation of presynaptic fibers (Figure 1a). The same
result was observed when glutamate uncaging was paired
with channelrhodopsin-induced depolarization of the
postsynaptic neuron [48]. In addition to these studies
demonstrating structural changes of existing spines, a
recent study demonstrated a de novo formation of new
spines after local glutamate uncaging in the dendrite [49].
Whether the diameter and length of the spine neck
change or not has not been confirmed using live imaging
techniques available so far. The recent development of
superresolution imaging methods will be key to answering this question [50,51,52,53,54].
Conversely, the induction of long-term depression
(LTD) by either electrical or chemical stimulation
induces shrinkage [47,55,56,57] or loss of dendritic
spines [47,58]. Spine shrinkage is persistent but reversible, as it can be reverted by a potentiation stimulus [55].
These studies on LTD and other recent studies on LTP
[59,60] show that structural plasticity can be dissociated
from functional plasticity. Although they share the same
initial triggering mechanisms, they seem to be regulated
by parallel but distinct downstream intracellular signaling
pathways. Thus, the role of morphological changes of
spines in synaptic transmission and plasticity still remains
an open question.
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Structural plasticity of dendritic spines Bosch and Hayashi 3
Figure 1
(a)
Tetanus
CFP
-10
-5
0
5
10
15
20
25
30
FRET
Higher FRET
0.5 µm
(b)
0.2 µm
Current Opinion in Neurobiology
Actin filaments in the dendritic spine. (a) Expansion of the dendritic spine and rapid polymerization of actin by local tetanic stimulation. Actin
polymerization was visualized by FRET-based imaging method, which detects the proximity of actin molecules. Obtained from [47]. (b) An electron
micrographic image of a dendritic spine showing S1-fragment labeled F-actin. Contrast was adjusted from the original, and coloring (red, spine head;
yellow, dendritic shaft) was added by the authors of this review. Arrowheads point to the spine neck. Obtained from [12].
F-actin regulation as a mechanism underlying
structural plasticity
What molecular mechanisms are responsible for the structural plasticity of dendritic spines? By decorating F-actin
with myosin subfragment 1 (S-1 fragment), Fifková et al.
demonstrated that actin filaments are associated with the
plasma membrane and the PSD at their barbed ends and
form a lattice structure within the spine head matrix [12]
(Figure 1b). By contrast, the actin filaments are organized
in long strands in the spine neck and dendritic shaft. This
finding was also confirmed by a recent EM study [61]. The
authors predicted that, given the dynamic properties of
actin, actin filaments play a crucial role in synaptic
plasticity, by changing the shape of the presynaptic and
postsynaptic side and, in neuronal circuits, by mediating
the retraction and sprouting of synapses [12].
Consistent with the important role of F-actin regulation in
synaptic plasticity, the pharmacological manipulation of
actin polymerization and depolymerization effectively
blocks LTP [62,63] and, at the same time, suppresses
the structural enlargement of dendritic spines [46].
The rapid polymerization of actin in spines during LTP
was demonstrated by a FRET-based method that detected
actin-actin interactions in real time [47] (Figure 1a). Using
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the same system, it was also demonstrated that LTD is
accompanied by depolymerization of F-actin [47].
Actin undergoes a rapid turnover in the spine, replacing
almost the entire molecular population every 2–3 min
[64,65]. Recent studies have revealed the fine details
of actin dynamics within dendritic spine subdomains by
using photoactivatable and photoswitchable fluorescent
protein-tagged actin [65,66]. They found that actin
undergoes a constant inward flow from the periphery to
the center of the spine on the order of minutes. Because
the speed of diffusion of monomeric actin (globular or Gactin) is expected to be much faster (on the order of
seconds), the observed fluorescence movement reflects
the treadmilling of F-actin, i.e., the movement of the
monomer within the filament while it polymerizes at one
side (the barbed end, mainly located at the periphery) and
depolymerizes at the other one (the pointed end, located
at the spine core; Figure 2a). This is consistent with the
polarity of actin filaments revealed by electron microscopic observation [12].
Importantly, stimulation of synaptic glutamate receptor
slows down F-actin turnover/treadmilling [64,65].
Furthermore, Honkura et al. found that LTP induction
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4 Synaptic Structure and Function
Figure 2
(a)
(b)
G-actin
barbed end
F-actin
(c)
G-actin
polymerization
F-actin
spine expansion
polymerization
polymerization
F-actin
pointed end
depolymerization
depolymerization
F-actin stability
depolymerization
F-actin stability
G-actin
Current Opinion in Neurobiology
Proposed mechanisms for spine expansion. (a) In a naive spine, there is a constant treadmilling of actin from the periphery to the center of the dendritic
spine, maintained by an equilibrated rate of F-actin polymerization/depolymerization. (b) LTP induction stabilizes the actin filaments and slows down
the depolymerization at the pointed end of F-actin located at the core of dendritic spine. (c) Polymerization continues in the periphery of dendritic
spine, thereby generating the driving force that expands the spine head.
leads to a formation of a new stable population of actin at
the core of the spine head [65]. This could be explained
by a reduced depolymerization rate from the pointed end
of the actin filament at the core of the spine. Polymerization would continue at the barbed end in the spine
periphery, thereby generating the force that enlarges the
dendritic spine. This effect would also be responsible for
the overall shift in G-actin/F-actin equilibrium towards
polymerization. We propose that this is the mechanism of
expansion of the dendritic spine during LTP (Figure 2b
and c).
It is therefore crucial to elucidate the signaling pathways
that regulate F-actin treadmilling during LTP to understand synaptic plasticity [67,68]. The blockade of
NMDA-type glutamate receptor (NMDAR) completely
inhibits structural LTP [46,47]. Inhibition of Ca2+/
calmodulin-dependent protein kinases (CaMK) partially
blocks the spine enlargement [46,69]. One of the major
members of the CaMK family present in the PSD,
CaMKIIb, bundles F-actin filaments independently of
its kinase activity. Interestingly, the activation of CaMKIIb by Ca2+/CaM inhibits this F-actin bundling
capacity [70]. Such ability may determine the time
window wherein F-actin can be reorganized [71]. A
recent imaging study detected a persistent activation
of the Rho family of small G-proteins in the dendritic
spine after LTP induction [72]. The pharmacological
blockade of downstream signaling pathway of these
proteins, including p21-activated kinase (PAK) and
Rho-associated, coiled-coil containing protein kinase
(ROCK), effectively blocked spine enlargement [72].
These pathways regulate the activity of several actinbinding proteins [68], such as profilin and cofilin, which
might ultimately be responsible for altering the rate of
actin polymerization/depolymerization and treadmilling
and, thus, for controlling spine morphology.
Concluding remarks
The development of new imaging and optical manipulation techniques allows us to visualize the behavior of
single dendritic spines during synaptic plasticity in great
temporal and spatial detail. This technology revealed a
novel aspect of hippocampal LTP, namely the structural
modification of the dendritic spine. There is a tight
correlation between the physiology of synaptic transmission and the shape of the dendritic spine, although
both phenomena could play distinct and complementary
functions in neuronal plasticity. The current development of more sophisticated imaging modalities combined
with molecular and electrophysiological methods will
further elucidate the fundamental role that the
morphology of the dendritic spine may play in the processes of learning and memory.
Acknowledgements
The authors dedicate this review to Eva Fifková (May 21, 1932–February 1,
2010). We thank Lily Yu for editing. This work was supported by RIKEN,
NIH grant R01DA17310, Grant-in-Aid for Scientific Research (A) and Grantin-Aid for Scientific Research on Innovative Area ‘Foundation of Synapse and
Neurocircuit Pathology’ from the MEXT, Japan (Y.H.). M.B. is a recipient of
a ‘Beatriu de Pinós’ fellowship from the ‘Generalitat de Catalunya’.
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Current Opinion in Neurobiology 2011, 22:1–6
Please cite this article in press as: Bosch M, Hayashi Y. Structural plasticity of dendritic spines, Curr Opin Neurobiol (2011), doi:10.1016/j.conb.2011.09.002
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