The Emerging Role of Mechanics in Synapse Formation and Plasticity

Abstract

The regulation of synaptic strength forms the basis of learning and memory, and is a key factor in understanding neuropathological processes that lead to cognitive decline and dementia. While the mechanical aspects of neuronal development, particularly during axon growth and guidance, have been extensively studied, relatively little is known about the mechanical aspects of synapse formation and plasticity. It is established that a filamentous actin network with complex spatiotemporal behavior controls the dendritic spine shape and size, which is thought to be crucial for activity-dependent synapse plasticity. Accordingly, a number of actin binding proteins have been identified as regulators of synapse plasticity. On the other hand, a number of cell adhesion molecules (CAMs) are found in synapses, some of which form transsynaptic bonds to align the presynaptic active zone (PAZ) with the postsynaptic density (PSD). Considering that these CAMs are key components of cellular mechanotransduction, two critical questions emerge: (i) are synapses mechanically regulated? and (ii) does disrupting the transsynaptic force balance lead to (or exacerbate) synaptic failure? In this mini review article, I will highlight the mechanical aspects of synaptic structures—focusing mainly on cytoskeletal dynamics and CAMs—and discuss potential mechanoregulation of synapses and its relevance to neurodegenerative diseases.

Full text

MINI REVIEW
published: 06 December 2018
doi: 10.3389/fncel.2018.00483
The Emerging Role of Mechanics in
Synapse Formation and Plasticity
Devrim Kilinc*
INSERM U1167, Institut Pasteur de Lille, Lille, France
Edited by:
Kyle Miller,
Michigan State University,
United States
Reviewed by:
Olivier Thoumine,
Centre National de la Recherche
Scientifique (CNRS), France
Brenton Hoffman,
Duke University, United States
*Correspondence:
Devrim Kilinc
devrim.kilinc@pasteur-lille.fr
Received: 01 September 2018
Accepted: 27 November 2018
Published: 06 December 2018
Citation:
Kilinc D (2018) The Emerging Role of
Mechanics in Synapse Formation
and Plasticity.
Front. Cell. Neurosci. 12:483.
doi: 10.3389/fncel.2018.00483
The regulation of synaptic strength forms the basis of learning and memory, and is a key
factor in understanding neuropathological processes that lead to cognitive decline and
dementia. While the mechanical aspects of neuronal development, particularly during
axon growth and guidance, have been extensively studied, relatively little is known
about the mechanical aspects of synapse formation and plasticity. It is established
that a filamentous actin network with complex spatiotemporal behavior controls the
dendritic spine shape and size, which is thought to be crucial for activity-dependent
synapse plasticity. Accordingly, a number of actin binding proteins have been identified
as regulators of synapse plasticity. On the other hand, a number of cell adhesion
molecules (CAMs) are found in synapses, some of which form transsynaptic bonds to
align the presynaptic active zone (PAZ) with the postsynaptic density (PSD). Considering
that these CAMs are key components of cellular mechanotransduction, two critical
questions emerge: (i) are synapses mechanically regulated? and (ii) does disrupting
the transsynaptic force balance lead to (or exacerbate) synaptic failure? In this mini
review article, I will highlight the mechanical aspects of synaptic structures—focusing
mainly on cytoskeletal dynamics and CAMs—and discuss potential mechanoregulation
of synapses and its relevance to neurodegenerative diseases.
Keywords: dendritic spine, cytoskeleton, cell adhesion molecules, motor proteins, mechanotransduction, synaptic
scaffold proteins
INTRODUCTION
Chemical synapses of the central nervous system (CNS) mediate the directional information flow
between neurons and form the basis of learning and memory. A precisely-defined synaptic cleft
separates the opposing pre- and postsynaptic terminals that are held in place via transsynaptic
cell adhesion molecules (CAMs). While presynaptic terminals are specialized in neurotransmitter
release, postsynaptic terminals house neurotransmitter receptors and various signaling and
scaffolding proteins. Functional diversity of synapses is reflected in structural diversity: most
inhibitory synapses form directly on the dendrite shaft, while most excitatory synapses form
on dendritic spines—morphologically diverse membrane protrusions from the dendrite shaft.
Dendritic spines may form enlarged heads with relatively narrow necks, resulting in signaling hubs
with restricted electrical and chemical connection to the dendrite shaft. The postsynaptic density
(PSD), a dense protein matrix beneath the postsynaptic membrane, forms at the tip of the spine
Abbreviations: ABP, actin-binding protein; AD, Alzheimer’s disease; AMPAR, α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor; APP, amyloid precursor protein; CAM, cell adhesion molecule; CaMKII, Ca2+/calmodulin-
dependent protein kinase; CNS, central nervous system; D1R, dopamine D1 receptor; ECM, extracellular matrix; F-actin,
filamentous actin; IgCAM, immunoglobulin superfamily cell adhesion molecule; LDP, long-term depression; LTP, long-term
potentiation; MMP, matrix metalloproteinase; NCAM, neural cell adhesion molecule; NMDAR, N-methyl-D-aspartate
receptor; PAZ, presynaptic active zone; PSD, postsynaptic density.
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Kilinc Mechanical Regulation of Synapses
head and orchestrates synaptic functions (Sheng and
Kim, 2011). The size and shape of individual spines are
regulated in an activity-dependent fashion, supported by
a specialized protein synthesis and degradation system
(Alvarez-Castelao and Schuman, 2015). Synapses may last
from seconds to decades; thus, highly sophisticated regulatory
mechanisms are required to effectively control their dynamics,
during development and adulthood.
The role of mechanics in neurodevelopment is best
characterized at the growth cones (Franze, 2013), highly
motile tips of growing axons that integrate mechanical and
chemical cues during axon pathfinding (Kerstein et al.,
2015). Much less is known about the mechanical aspects of
synapse formation and plasticity. This is—partly—due to
the increased complexity of mature neurons compared to
developing axons. Nevertheless, recent studies established that
synapse formation and plasticity require unique mechanisms
involving the cytoskeleton, molecular motors, CAMs and the
extracellular matrix (ECM; Figure 1). Considering that these
components are either force-generating or force-bearing, two
critical questions emerge: (i) are synapses mechan(ochem)ically
regulated? and (ii) does disrupting the transsynaptic force
balance lead to (or exacerbate) synaptic failure? In this mini
review article, I will highlight the mechanical aspects of synaptic
structures—focusing mainly on cytoskeletal dynamics and
CAMs—and discuss potential mechanoregulation of synapses
and its relevance to neurodegenerative diseases.
DYNAMIC CYTOSKELETAL
INTERACTIONS SHAPE SYNAPSES
The cytoskeleton is an interconnected network of dynamic
filaments and regulatory proteins mediating not only the
mechanical processes such as shape change and cell motility,
but also the global intracellular organization. This is achieved
through combining stable, long-range interactions and highly
dynamic, short range interactions (Fletcher and Mullins, 2010).
Synapses rely on cytoskeletal processes to accomplish specific
tasks, from activity-dependent structural change to long-term
maintenance of established connections. I will discuss actin,
microtubule and neurofilament networks separately, despite the
tight coupling between them (Coles and Bradke, 2015).
Dynamic Actin Networks Control Dendritic
Spine Shape and Size
Dendritic spines are structurally supported by a filamentous
actin (F-actin) framework, which controls the spine shape and
organizes the signaling machinery (reviewed in Hotulainen
and Hoogenraad, 2010). The F-actin retrograde flow in spines,
i.e., from tip to base, is reminiscent of the same in developing
axons (Nichol et al., 2016), albeit with shorter filaments and
lower flow rates (∼50 nm/s; Frost et al., 2010). However,
this resemblance is disputed by reports showing that the
F-actin flow slows down (from ∼35 nm/s to ∼20 nm/s) as
dendritic filopodia turn into spines (Chazeau et al., 2014),
and that the polarization is lost (Tatavarty et al., 2012).
Long-term potentiation (LTP) and depression (LTD) induce
FIGURE 1 | Mechanically-relevant components of an excitatory synapse.
Presynaptic vesicle fusion machinery and postsynaptic receptors are held in
place by their respective scaffold proteins, which are physically linked to cell
adhesion molecules (CAMs) and the cytoskeleton. Direct interactions are
indicated with thin, continuous arrows. Translational movements are indicated
with thin, broken arrows. Only postsynaptic cytoskeleton is depicted for
simplicity. Major cytoskeletal filaments (actin, neurofilaments, microtubules)
and a select set of associated molecules (microtubule end-binding protein
EB3, actin severing/stabilizing protein cofilin, actin branch-inducing
Arp2/3 complex) are depicted. Spine base and center are occupied by stable,
dense F-actin, whereas the periphery is occupied by dynamic, branched
F-actin. F-actin rings line the spine shaft. Microtubules occasionally invade
spines and interact with the postsynaptic density (PSD), but the role of
neurofilaments is not clear. Actin and microtubule polymerization creates
tensile forces (green arrows) favoring the expansion of the spine head. Myosin
motors pull on actin filaments to generate actomyosin contractile forces (red
arrows) favoring the shrinkage of the spine head. Kinesin and dynein motors
transport cargo on microtubules anterograde and retrograde, respectively. The
latter also interacts with the PSD. A select set of CAMs are depicted, most of
which form transsynaptic homophilic bonds. N-cadherin and SynCAM bonds
encircle the presynaptic active zone (PAZ) and the PSD. β-catenin links
N-cadherin to the F-actin cytoskeleton directly or via α-catenin and vinculin.
This linkage pulls on transsynaptic CAM bonds, which potentially induce
signaling in pre- and postsynaptic compartments, i.e., mechanotransduction.
Powered by actomyosin contractile forces, integrins pull on the extracellular
matrix (ECM), where force is transmitted via the focal adhesion complex (of
which vinculin is a member). The force balance between CAMs and the actin
cytoskeleton results in actin retrograde flow and allows for the rapid
expansion/shrinkage of the spine structure. Not drawn to scale.
actin polymerization and depolymerization in spines causing
them to enlarge or shrink, respectively (Bosch and Hayashi,
2012). Three distinct pools of F-actin occupy the dendritic spines:
a stable core, forming the center and the base, a dynamic shell,
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Kilinc Mechanical Regulation of Synapses
extending towards the periphery, and an apical pool associated
with the head enlargement during LTP (Honkura et al., 2008).
In addition, there are periodic F-actin rings that shape the
spine neck (Bär et al., 2016). The dynamic and stable pools
have drastically different turnover rates, i.e., polymer half-life of
tens of seconds vs. tens of minutes (Stefen et al., 2016). These
differences in F-actin dynamics likely arise from the distinct
spatiotemporal organization of various actin-binding proteins
(ABPs) in dendritic spines.
Multiple ABPs regulate F-actin in dendritic spines: cortactin
and drebrin localize to the stable core, whereas cofilin localizes to
the dynamic shell (Rácz and Weinberg, 2013). Cortactin directly
interacts with N-methyl-D-aspartate receptors (NMDARs) and
Shank scaffold in the PSD, and regulates the branch-inducing
Arp2/3 complex (Hering and Sheng, 2003), which is required
for spine maturation (Spence et al., 2016). During LTP, the
actin severing protein cofilin is rapidly recruited into the spine
and forms stable complexes with F-actin (as cofilin’s effect
paradoxically shifts from severing to stabilizing with increasing
stoichiometric ratio), which occupy the base of spines and
consolidate their expansion (Bosch et al., 2014). Importantly,
cofilin regulates NMDA-dependent synapse remodeling in LTP
and LTD (Pontrello et al., 2012). Altogether, these data suggest
that actin is the primary structural element in postsynapses.
Microtubules Transiently Invade Dendritic
Spines (Not Only) for Cargo Delivery
Microtubules transiently invade mature spines (residing there
for a few minutes) and the occurrence and duration of these
invasions correlate with neuronal activity (Hu et al., 2008).
Transient nature and activity-dependence of microtubule spine
invasions suggest that they drive cargo in and out; e.g., kinesin-3
delivers synaptotagmin-IV, an LTP regulator, to spine heads
(McVicker et al., 2016). Mitochondria, however, undergo an
actomyosin handoff, i.e., switch from microtubule-based to
actin-based motor transport, to reach the spine head. Similarly,
recycling endosomes containing α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid receptors (AMPARs) are transported
into spines via myosins Va (Correia et al., 2008) and Vb (Wang
et al., 2008). During LTP they undergo syntaxin-4-mediated
exocytosis such that AMPAR are inserted into the plasma
membrane adjacent to the PSD (Kennedy et al., 2010). However,
to what extent AMPAR are actively transported and/or diffuse
laterally into the spine head is debated (Penn et al., 2017). Apart
from retrogradely transporting neurotrophic factors, dendritic
kinesin-4 also regulates microtubule dynamics (Ghiretti et al.,
2016), and is required for learning and memory (Muhia et al.,
2016).
The microtubule plus end-binding protein EB3 directly
interacts with the postsynaptic scaffold protein PSD-95, an
event that decreases EB3-microtubule interaction (Sweet et al.,
2011), suggesting a functional role for dendritic microtubules
in synaptic plasticity. Indeed, spine invasion by EB3-capped
microtubules constrains the ABP p140CAP to the PSD and
maintains the spine size (Jaworski et al., 2009). Accordingly,
during LTD, NMDAR-mediated Ca2+influx removes EB3 from
growing microtubule tips, which causes EB3 accumulation in the
dendrite shaft and suppresses microtubule entry into the spine
(Kapitein et al., 2011). Interestingly, microtubule spine invasions
require a cortactin-dependent increase in the F-actin remodeling
at the base of the synapse, but do not require EB3- and drebrin-
mediated F-actin-microtubule linkages (Schätzle et al., 2018).
Altogether, these studies suggest that microtubules indirectly
regulate synapses via transporting cargo and regulating the actin
cytoskeleton.
Neurofilaments—Additional Structural
Support for Postsynaptic Density?
Neurofilaments are neuron-specific intermediate filaments
associated with axon caliber regulation (Lee and Cleveland,
1996). All four neurofilament subunits found in the CNS—NF-L,
NF-M, NF-H and α-internexin—localize to the synapses
(enriched in postsynapses), are distinct from their axonal
counterparts, and have no known functions (Yuan et al., 2015).
Neurofilaments—but not F-actin or microtubules—directly
interact with SAPAP (Hirao et al., 2000), a member of PSD-
95/SAPAP/Shank core complex, the major scaffold of the PSD
(Zhu et al., 2017). Mice lacking neurofilament subunits have
structurally normal brains, but exhibit synapse plasticity and
memory deficits, indicating a functional role. In support of this,
dopamine D1 receptor (D1R)-induced LTP was modulated by
NF-M, which anchors D1R-containing endosomes to build up
a reservoir of D1Rs for their rapid recycling to the postsynaptic
membrane (Yuan et al., 2015). Curiously, the cytoplasmic tail of
NR1 subunit of NMDAR binds neurofilaments and inhibits their
assembly (Ehlers et al., 1998), consistent with the findings that
synaptic vesicles and endosomes dock onto neurofilament-based
scaffolds, and that vesicle recycling requires neurofilaments to
interact with microtubule motors (Yuan et al., 2017). While
these data suggest that neurofilaments mainly act as postsynaptic
scaffolds, further effort is required to decipher the specific
synaptic function(s) of their subunits.
CELL ADHESION MOLECULES INITIATE,
SPECIFY AND REGULATE SYNAPSES
CAMs are cell surface molecules that link cells to the ECM and to
other cells via homophilic and heterophilic interactions. Synaptic
CAMs are defined as CAMs with potential to induce synapses
via trans interactions (Frei and Stoeckli, 2014). However, other
CAMs also localize to synapses and contribute to synapse
formation and plasticity, through transsynaptic recognition and
signaling processes, respectively (Dalva et al., 2007). In fact, the
subtype of the CAM(s) recruited can determine the synapse
type: for example, alternative splicing of postsynaptic neuroligins
leads to either inhibitory or excitatory synapses (Chih et al.,
2005). CAMs are hierarchically expressed; some are required
for core synaptic functions and others for specialized functions.
Moreover, ‘‘early’’ and ‘‘late’’ synaptic genes are co-expressed and
co-regulated in the same neuron, suggesting that their differential
localization and combinatorial use define synapse specificity and
network connectivity rules (Földy et al., 2016). Here, I will
describe the major CAM families involved; for a complete list of
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Kilinc Mechanical Regulation of Synapses
CAMs in synapses, see recent reviews (Jang et al., 2017; Chamma
and Thoumine, 2018).
Integrins Regulate Functional and
Structural Plasticity of Dendritic Spines
Integrins are heterodimeric transmembrane receptors that link
ECM components to the actin cytoskeleton via adaptor proteins,
e.g., talin and vinculin, forming a ‘‘molecular clutch’’ that
transmits actomyosin contractile forces to the ECM (Sun
et al., 2016). Integrins regulate the spine functional plasticity
through controlling receptor trafficking in a subunit-specific
manner: α3β1-integrins regulate LTP through modulating
NMDAR activity (Chan et al., 2007), whereas αVβ3-integrins
regulate synaptic strength through stabilizing AMPAR in the
membrane (Cingolani et al., 2008). LTP induces long-lasting
(∼30 min) Rho activity in individual spines that is thought
to relay the transient activation of Ca2+/calmodulin-dependent
protein kinase II (CaMKII; ∼10 s to structural plasticity
(Murakoshi et al., 2011). Rho and Rac act at different
phases of LTP, mediating the spine neck formation and
driving the spine head expansion, respectively (Rex et al.,
2009). In fact, while ROCK1 regulates the early phase by
forming stable actomyosin bundles that create spine polarity,
ROCK2 regulates the late phase by controlling Rac activity and
by deactivating cofilin (Newell-Litwa et al., 2015). Rac1 activity,
in turn, maintains the globular shape of the spine through
regulating the localization and dynamics of the branched
F-actin network (Chazeau et al., 2014). Separately, integrins
regulate the spine structural plasticity through controlling
actin remodeling: the integrin/focal adhesion pathway regulates
multiple ABPs, including Arp2/3 complex (Serrels et al.,
2007), cortactin (Hotulainen and Hoogenraad, 2010) and
cofilin (Heredia et al., 2006). Together, these studies suggest
that integrins regulate synapses through multiple, intertwined
mechanisms. Moreover, recent proteomic analyses identified
new, non-canonical adhesion components with emerging
functions in mechanotransduction and receptor trafficking
(Humphries et al., 2015). Their potential roles in synapse
formation and plasticity are yet to be explored.
Cadherin/Catenin Complexes Are
Important Regulators of Synapse Plasticity
Cadherins are Ca2+-dependent transmembrane proteins found
at intercellular adherent junctions. Their ectodomains form
homo- and occasional heterophilic bonds and their intracellular
tails interact with various partners—notably catenins and
vinculins—to induce downstream signaling. Cadherins can form
transsynaptic bonds with different adhesiveness and kinetics,
thanks to their large repertoire of homophilic interactions: trans
dimers (slip bond), X-dimers (catch bond) and clusters, which
combine cis and trans bonds (Leckband and de Rooij, 2014).
Cadherin mechanotransduction is highly complex (reviewed
in Hoffman and Yap, 2015): on one hand, cadherin-catenin
complex directly interacts with F-actin via a two state catch
bond (that strengthens under force, as opposed to slip bonds
that weaken under force), reinforcing intercellular adhesion
(Buckley et al., 2014). On the other hand, force induces a
conformational change in α-catenin, revealing cryptic sites
for vinculin binding. Activated vinculin not only directly
binds to F-actin, but also recruits Ena/VASP family proteins
to promote actin assembly, further reinforcing the cadherin-
cytoskeleton coupling (le Duc et al., 2010). In the CNS, classical
cadherins (e.g., N-cadherin) localize to pre- and postsynapses,
and border the presynaptic active zone (PAZ; Uchida et al., 1996).
During development, neuron-neuron interactions regulate the
activity-dependent dendrite arborization, which is mediated by
cadherin/catenin surface levels (Tan et al., 2010). It should
be noted that, due to structural differences, N-cadherin and
E-cadherin dimers have different disassembly kinetics, where
the former depend strongly on Ca2+binding and cannot
form X-dimers (Vunnam and Pedigo, 2012). It is therefore
likely that N-cadherin and E-cadherin have distinct mechanical
behavior. Similarly, αN-catenin differs from αE-catenin in terms
of β-catenin binding kinetics (Pokutta et al., 2014), further
suggesting that mechanotransduction mechanisms identified for
E-cadherin/αE-catenin may not be applicable to synapses.
Cadherins take part in spine and synapse formation,
particularly in excitatory neurons (Seong et al., 2015). In
postnatal, excitatory synapses, N-cadherin is required for
LTP and spine enlargement—but not LTD or spine density
and morphology, suggesting that cadherins selectively regulate
synapse plasticity (Bozdagi et al., 2010). Indeed, cadherin
accumulation on synaptic membranes is required for stabilizing
postsynaptic receptors, e.g., kainate receptors (Fièvre et al., 2016)
and AMPAR (Mills et al., 2017). Catenins also regulate synapses:
upon NMDAR activation, β-catenin is redistributed from the
dendrite shaft to the spines (where it binds N-cadherin), leading
to synapse enlargement, consistent with its role in learning and
memory (Murase et al., 2002). Furthermore, spines compete for
surface-bound N-cadherin/β-catenin complexes, which appear
to be the key drivers for activity-dependent spine pruning,
where β-catenin redistribution determines the fate of individual
spines, i.e., stabilizing one while eliminating its neighbors (Bian
et al., 2015). Cumulatively, these data suggest that cadherin and
its intracellular binding partners are important regulators of
synapse plasticity.
Several Other CAM Families Localize to
Synapses
Ectodomains of the immunoglobulin superfamily CAM
(IgCAM) contain tandem repeats of Ig-like domains, which
permit the formation of a variety of trans and cis bonds,
leading to molecular zippers (Aricescu and Jones, 2007). Such
flexibility is ideal for mechanosignaling, where force-induced
conformational change regulates intracellular signaling (Johnson
et al., 2007). For example, neural CAM (NCAM)—critical
for neurodevelopment (Maness and Schachner, 2007)—forms
at least two types of homophilic bonds differing in force
sensitivity and intercellular distance (Wieland et al., 2005).
NCAM regulates synapses by crosslinking to NMDAR and
CaMKII via a spectrin-based postsynaptic scaffold (Sytnyk et al.,
2006). Additionally, NCAM interacts with dynein to tether
microtubule plus-ends, an event that enhances synapse stability
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Kilinc Mechanical Regulation of Synapses
(Perlson et al., 2013). SynCAM, originally identified as an
IgCAM promoting synaptogenesis (Biederer et al., 2002), forms
transsynaptic homophilic bonds at spine heads encircling the
synaptic cleft (Perez de Arce et al., 2015). Importantly, SynCAM
complexes enlarge during LTD, suggesting that they control the
cleft diameter.
Presynaptic neurexins interact with postsynaptic neuroligins,
which directly bind to and recruit PSD-95—a function regulated
through phosphorylation (Giannone et al., 2013; Bemben et al.,
2014). The neurexin-neuroligin bond stabilizes the dendritic
filopodia during synaptogenesis (Chen et al., 2010), and regulates
the synapse specificity in an isoform-dependent manner (Graf
et al., 2004; Boucard et al., 2005). In fact, neurexins are
heparan sulfate proteoglycans and neuroligin binding to heparan
sulfate chains on neurexin is necessary for synapse development
(Zhang et al., 2018). In mature synapses, NMDAR activation
leads to juxtamembrane cleavage of neuroligin by matrix
metalloproteinase 9 (MMP-9) or by ADAM10, which destabilizes
neurexins and decreases synaptic strength by altering presynaptic
release (Peixoto et al., 2012; Suzuki et al., 2012).
Another CAM type required for synapse specificity is the
clustered protocadherin (Kostadinov and Sanes, 2015). Clustered
protocadherins form homodimers and antiparallel homophilic
trans interactions to regulate dendritic self-avoidance (Nicoludis
et al., 2015). Unfortunately, whether CAMs other than integrins
and cadherins participate in the mechanotransduction is largely
unknown. One exception to this is the ephrin-Eph receptor
pair, which bidirectionally regulates synapse formation and
maturation in the adult, i.e., ephrins can signal into the
Eph-receptor-expressing cell (forward) or into their host cell
(reverse; reviewed in Klein, 2009). For example, the dynamics
of EphB2 kinase activity at the tip of a dendritic filopodium
upon binding to axonal ephrin-B1 determines whether the
filopodium retracts or establishes a synapse (Mao et al., 2018).
On the other hand, dendritic ephrin-B3 directly interacts with
PSD-95 to control its localization and stability, via activity-
dependent phosphoregulation (Hruska et al., 2015). Importantly,
physically restraining the ephrin-A1 modulates cytoskeletal
dynamics by blocking the EphA2 receptor clustering, indicating
that ephrin-Eph pair is mechanosensitive (Salaita et al., 2010).
Together, these data suggest that mechanotransduction via
CAMs may be a general mechanism in synapse regulation, and
not unique to integrins and cadherins.
OTHER POTENTIAL
MECHANOREGULATORS OF SYNAPSE
PLASTICITY: SCAFFOLD PROTEINS,
MECHANOSENSITIVE ION CHANNELS,
AND THE EXTRACELLULAR MATRIX
Apart from major mechanical actors (cytoskeleton, CAMs),
synapses contain other mechanically-relevant components.
Synaptic scaffolds support the dynamic components of the
PAZ and the PSD (Ziv and Fisher-Lavie, 2014) and, since
they physically couple CAMs to the underlying cytoskeleton,
they potentially bear tensile forces. While non-specifically
pulling on a neurite is sufficient to recruit Bassoon presynaptic
scaffold into a potential presynapse (Suarez et al., 2013), the
mechanosensitivity of scaffold proteins remains unknown.
Mechanosensitive ion channels, however, are expressed in
neurons (Hu et al., 2015), although most do not localize to
synapses. An important exception to this is NMDAR, which
may be activated through increased membrane tension (Paoletti
and Ascher, 1994) or by cytoskeletal forces acting on its
intracellular domain (Singh et al., 2012). The ECM is another
potential mechanoregulator of synapses: the composition,
structure and stiffness of the ECM (reciprocally) regulate
the cellular mechanotransduction (reviewed in Humphrey
et al., 2014). Components of the ECM form a perineuronal
net that surrounds dendritic spines and extends into the
synaptic cleft (Dansie and Ethell, 2011). In the adult brain,
chondroitin sulfate proteoglycans stabilize dendritic spine
structure and movement, whereas, other glycoproteins
(notably, reelin, agrin and tenascins) are important regulators
of synapse plasticity (reviewed in Levy et al., 2014). For
example, cleavage of agrin (an integrin αvβ1ligand) by
neurotrypsin promotes LTP by facilitating new dendritic
filopodia (Matsumoto-Miyai et al., 2009). Similarly, cleavage
of the hyaluronan receptor CD44 by MMP-9, results in its
detachment from the ECM and leads to dendritic spine
elongation (Bijata et al., 2017). These data suggest that ECM
proteolysis regulates synapses, potentially by modifying their
force balance.
IS SYNAPSE PLASTICITY MECHANICALLY
REGULATED?
As illustrated above, mechanotransduction takes place during
synapse plasticity. It is clear that mechanical processes convey
biochemical signals into spine remodeling; however, whether
they also convey purely mechanical signals (e.g., forces with a
certain magnitude, rate, duration and frequency; Hoffman et al.,
2011) to invoke structural change is unknown. In fact, changes
in plasma membrane curvature and tension (due to spine
remodeling) may be sufficient to induce mechanotransduction
(Diz-Muñoz et al., 2013). Identifying such mechanisms remains
a challenge due to the high level of complexity, i.e., synapses
involve numerous CAMs—some of which crosstalk via common
effectors (Mui et al., 2016)—and intertwined cytoskeletal
networks (Figure 1). Since pulling on a transsynaptic CAM
(e.g., cadherin) bond modulates not only its unbinding rate,
but also its downstream signaling by revealing cryptic domains
(e.g., α-catenin-vinculin interaction), the acting force needs to be
tightly controlled, such that intracellular signaling precedes bond
breakage.
Notably, cadherin transsynaptic bonds can be synapse-
specific: synapses between hippocampal CA3 and CA1 neurons
with high-magnitude LTP require cis dimers of postsynaptic
cadherins-6 and -10 to form trans bonds with presynaptic
cadherin-9 (Basu et al., 2017). This level of complexity
suggests mechanosignaling to take place, considering the
differences in the force-dependency of these bonds. Indeed,
N-cadherins stabilize filopodial F-actin through counteracting
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Kilinc Mechanical Regulation of Synapses
the actomyosin pulling force—a process associated with the
transition of the dendritic filopodia into spines (Chazeau
et al., 2015). Remarkably, pulling on N-cadherins at the tips of
dendritic filopodia—via optical tweezers—resulted in rapid actin
accumulation and mushroom-like spine morphology (Chazeau
et al., 2015), suggesting that cadherin mechanotransduction
alone can trigger synapse remodeling. Nevertheless, to
what degree mechanotransduction and signal transduction
mechanisms overlap, whether their activation is synchronized,
and whether they operate synergistically (e.g., to strengthen
synaptic signaling) remain open questions.
IS SYNAPSE MECHANICS RELEVANT TO
NEURODEGENERATIVE DISEASES?
Whether synapse mechanics is relevant to neurodegenerative
diseases is another open question. Synaptic failure is a key event
in most neurodegenerative diseases, particularly in Alzheimer’s
disease (AD). Accordingly, cytoskeletal proteins, including
cofilin (Rahman et al., 2014), drebrin (Gordon-Weeks, 2016)
and NF-L (Bacioglu et al., 2016) were implicated in AD
pathophysiology. Separately, multiple CAMs, including integrin
(Caltagarone et al., 2007), N-cadherin (Andreyeva et al., 2012),
NCAM (Leshchyns’ka et al., 2015) and neurexin-neuroligin
(Brito-Moreira et al., 2017) are involved in amyloid-β-induced
synaptotoxicity, a major event in AD. In fact, amyloid precursor
protein (APP), whose cleavage products include amyloid-β, is a
transsynaptic CAM (Ludewig and Korte, 2016). APP regulates
the PAZ organization (Laßek et al., 2016) and the dendritic spine
shape (Weyer et al., 2014), and its dimerization is regulated
by N-cadherin (Asada-Utsugi et al., 2011). These observations
suggest a link between synapse mechanics and synaptic failure
in AD, but direct evidence is missing.
CONCLUSIONS AND OUTLOOK
In this mini review article, I attempted to highlight the
mechanically-relevant mechanisms that take part in synapse
formation and plasticity. Growing evidence suggests that
synapses employ mechanosensitive molecules and mechanical
processes; however, direct evidence for the mechanoregulation
of synapse behavior is currently lacking. Implementing new
technologies for force application or measurement (Kilinc et al.,
2015), combined with novel single-molecule or super-resolution
approaches (Jin et al., 2018) may help discover such mechanisms.
To this end, magnetic tweezers would be an excellent tool
to specifically-target CAMs on dendritic filopodia (or axon
shafts) and to deliver well-defined forces to identify stretch
paradigms leading to spine (or PAZ) formation. Downstream
effects of the mechanical input may be monitored live in
terms of: (i) cytoskeletal dynamics; (ii) activity of cytoskeleton-
associated (e.g., ABPs) or signaling proteins (e.g., CaMKII); and
(iii) secondary messengers, such as Ca2+or cyclic nucleotides
(Blasiak et al., 2017). Notably, the frequency of local Ca2+
transients in dendritic filopodia upon initial contact with an
excitatory axon determines whether the connection will be lost
or stabilized (Lohmann and Bonhoeffer, 2008), suggesting that
Ca2+may be an intermediary to mechanical signaling. Finally,
single-molecule tension sensors (Cost et al., 2015) may be used
to identify load-bearing proteins in synapses during activity-
dependent remodeling, as well as to measure forces acting on
these proteins as a function of spine size and shape. A better
understanding of synapse mechanoregulation could pave the way
for mechanically modulated therapies against synaptic failure.
AUTHOR CONTRIBUTIONS
DK wrote the manuscript.
FUNDING
This work was funded by the 2017 Pilot Research Grant from
Fondation Vaincre Alzheimer and by the EU Joint Programme—
Neurodegenerative Diseases Research (JPND; 3DMiniBrain).
ACKNOWLEDGMENTS
I would like to thank Esther Stoeckli, Beatriz Rico, Marina
Mikhaylova and Agata Blasiak for critical reading of the
manuscript.
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