974313

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NROXXX10.1177/1073858420974313The NeuroscientistArriagada-Diaz et al.

Review
The Neuroscientist

Dynamin Superfamily at Pre- and

1­–18
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DOI: 10.1177/1073858420974313
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Synaptic Transmission and Plasticity journals.sagepub.com/home/nro

in Health and Disease

Jorge Arriagada-Diaz1,2*, Lorena Prado-Vega1,2*, Ana M. Cárdenas Díaz1,

Alvaro O. Ardiles1,3,4, and Arlek M. Gonzalez-Jamett1

Abstract
Dynamin superfamily proteins (DSPs) comprise a large group of GTP-ases that orchestrate membrane fusion and
fission, and cytoskeleton remodeling in different cell-types. At the central nervous system, they regulate synaptic vesicle
recycling and signaling-receptor turnover, allowing the maintenance of synaptic transmission. In the presynapses, these
GTP-ases control the recycling of synaptic vesicles influencing the size of the ready-releasable pool and the release of
neurotransmitters from nerve terminals, whereas in the postsynapses, they are involved in AMPA-receptor trafficking
to and from postsynaptic densities, supporting excitatory synaptic plasticity, and consequently learning and memory
formation. In agreement with these relevant roles, an important number of neurological disorders are associated with
mutations and/or dysfunction of these GTP-ases. Along the present review we discuss the importance of DSPs at
synapses and their implication in different neuropathological contexts.

Keywords
endocytic synaptic vesicle recycling, neurosecretion, AMPAR trafficking, synaptic plasticity, excitatory synapses,
dendritic spines, synaptopathies, dynamin superfamily, dynamin GTP-ase activity

Introduction 2020) and microtubule-instability (Hamao and others

Dynamin superfamily proteins (DSPs) are mechano-
enzymes with GTP-ase activity that catalyze membrane
remodeling (Antonny and others 2016; Ferguson and De
Camilli 2012; Gonzalez-Jamett and others 2013b;
Gonzalez-Jamett and others 2014; Praefcke and McMahon
2004; Singh and others 2018) during different cellular
processes including clathrin-mediated endocytosis (CME)
(Damke and others 1994; Loerke and others 2009;
Rappoport and Simon 2003; van der Bliek and others
1993; Warnock and Schmid 1996), caveolae internaliza-
tion (Henley and others 1998), exocytosis (Gonzalez-
Jamett and others 2010; Gonzalez-Jamett and others
2013a; Wong and others 2015), endosomal recycling
(Nicoziani and others 2000), post-trans-Golgi network
transportation of secretory vesicles to the plasma mem-
brane (Jones and others 1998; Kreitzer and others 2000)
and mitochondria fusion and fission (Mears and others
2011). In addition, DSPs are involved in membrane-inde-
pendent processes such as actin cytoskeleton dynamics
(Gonzalez-Jamett and others 2013a; Gonzalez-Jamett
and others 20117; Gu and others 2010; Mooren and oth-
ers 2009; Yamada and others 2013; Zhang and others
2009; Ishida and others 2011; Maeda and others 1992).
In mammals, classical dynamins are encoded by
three genes: DNM1, DNM2, and DNM3 located in
chromosomes 9 (Newman-Smith and others 1997), 19
(Zuchner and others 2005), and 1 (Noakes and others
1999), respectively. These genes can be subjected to
alternative splicing, producing each one from four to
thirteen spliced variants (Cao and others 1998). These
1
Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad
de Valparaíso, Valparaíso, Chile
2
Programa de Magister en Ciencias, mención Neurociencia,
Universidad de Valparaíso, Valparaíso, Chile
3
Centro de Neurología Traslacional, Facultad de Medicina,
Universidad de Valparaíso, Valparaíso, Chile
4
Centro Interdisciplinario de Estudios en Salud, Facultad de Medicina,
Universidad de Valparaíso, Viña del Mar, Chile
*These authors contributed equally to this work.
Corresponding Author:
Arlek M. Gonzalez-Jamett, Centro Interdisciplinario de Neurociencia
de Valparaíso, Universidad de Valparaíso, Gran Bretaña 1111 Playa
Ancha, Valparaiso, 2340000, Chile.
Email: arlek.gonzalez@cinv.cl
2 The Neuroscientist 00(0)

Figure 1.  Structure and assembly of dynamin superfamily proteins (DSPs). (A) Domains of classical dynamins and dynamin-
related proteins are schematized. Classical dynamins are composed by a GTP-ase domain, a middle domain, a pleckstrin
homology domain (PHD), a GTP-ase effector domain (GED), and a proline-rich domain (PRD). Dynamin-related proteins lack
PHD and PRD but include an “insert” variable sequence. The “bundle signaling element” (BSE) formed by helices from GTP-ase
and GED, together with the “stalk” region formed by helices from MD and GED mediate GTP-dependent dynamin self-assembly.
(B) Schematic representations of dimers and tetramers showing the interfaces required for dynamin’s oligomerization.

three dynamin isoforms exhibit different expression pat-
terns. While dynamin-1 is exclusively expressed in neu-
ronal tissues, dynamin-2 is ubiquitous, and dynamin-3
is present in brain, heart, testis, and lungs (Ferguson and
De Camilli 2012; Gonzalez-Jamett and others 2014;
Singh and others 2018). As outlined in Figure 1A, clas-
sic dynamins are composed by five conserved domains:
an amino-terminal catalytic GTP-ase domain (GD), a
middle domain (MD) required for their self-assembly, a
phosphoinositides-binding pleckstrin homology domain
(PHD), a GTP-ase-effector domain (GED), and a car-
boxy-terminal proline- and arginine-rich domain (PRD)
that binds SH3 domain-containing partners (Antonny
and others 2016; Ferguson and De Camilli 2012;
Gonzalez-Jamett and others 2013a; Gonzalez-Jamett
and others 2014; Praefcke and McMahon 2004; Singh
and others 2018). Three helices located on the N- and
C-terminus of GD together with a C-terminus helix
from GED form the “bundle signaling element” (BSE)
(Chappie and others 2009). Helices from the MD and
the amino-terminal portion of GED constitute the
“stalk” region (Antonny and others 2016; Chappie and
others 2009; Ford and others 2011) (Fig. 1) The BSE
seems to sense and convey GTP-dependent conforma-
tional changes from the GD to the stalk region, control-
ling dynamin’s activity (Chappie and others 2009). In
turn, depending on the information received from the
BSE, the stalk region mediates dynamin oligomeriza-
tion (Wenger and others 2013). In this regard, stalks
from neighboring monomers interact in an extensive
Arriagada-Diaz et al. 3
interface (interface 2) forming a cross-shaped dimer
with their GDs linked to one side of the cross, and their
PHDs linked to the other side (Chappie and others 2011;
Faelber and others 2011; Kong and others 2018) (Fig.
1B) In the absence of lipids, dynamins exist predomi-
nantly as tetramers, which are also stabilized by stalk-
localized interfaces (1 and 3). While interface 1 is at the
tips of interacting stalks, proximal to GD and BSE,
interface 3 is at the distal membrane–facing ends of the
interacting stalks (Chappie and others 2011; Faelber and
others 2011; Ford and others 2011; Kong and others
2018) (Fig. 1B).
In the presence of lipids dynamins form higher order
helical and ring-like structures (Hinshaw and Schmid
1995) that have up to 100-fold higher GTP-ase activity
(Warnock and Schmid 1996). In a GTP hydrolysis
dependent manner, dynamin-oligomers constrict, favor-
ing membrane tubulation and scission (Antonny and
others 2016). Factors such as low ionic strength
(Hinshaw and Schmid 1995) or the presence of negative
tubular templates such as lipid membranes (Lin and oth-
ers 1997; Salim and others 1996), microtubules (Maeda
and others 1992) and actin bundles (Gu and others 2010;
Mooren and others 2009) have shown to potentiate
dynamin oligomerization promoting its catalytic activ-
ity and membrane fission property. Besides classical
dynamins, DSPs also include dynamin-related proteins
(DRPs) which lack PHD and/or PRD (Williams and
Kim 2014) but exhibit important structural (Fig. 1A)
and functional similarities. In fact, DRPs are predicted
to carry out membrane tubulation and scission in a simi-
lar manner to the classical dynamins, exerting important
roles in intracellular trafficking (Bonekamp and others
2010), endocytosis and mitochondria fusion and seg-
mentation (Mears and others 2011).
In the nervous system, different types of DSPs are
expressed at the pre- and postsynaptic levels and partici-
pate in several processes modulating synaptic transmis-
sion. In presynaptic compartments, classical dynamins
play a key function supporting synaptic vesicle (SV)
recycling (Ferguson and others 2007; Raimondi and oth-
ers 2011; Tanifuji and others 2013) and they appear to
exert differential roles in response to different patterns of
neuronal activity (Tanifuji and others 2013). At the post-
synaptic level, they regulate the surface availability of
neurotransmitter receptors by tuning receptor turnover
(Carroll and others 1999; Kabbani and others 2004).
Consistently, dysfunctions of DSPs associate with a con-
siderable number of peripheral (PNS) and central nervous
system (CNS) disorders, including Charcot-Marie-Tooth
neuropathy (Zuchner and others 2005), centronuclear
myopathy (Bitoun and others 2005; Bitoun and others
2009), encephalopathy and epilepsy (Li and others 2015;
von Spiczak and others 2017), stroke and vascular
dementia (Mulugeta and others 2014), and sporadic forms
of Alzheimer’s disease (AD) (Aidaralieva and others
2008; Baek and others 2017; Kamagata and others 2009;
Kandimalla and others 2017).
In the current review, we discuss the importance of
DSPs at central synapses, with special attention on their
roles at the pre- and postsynaptic compartments and their
implication in neuropathological contexts.
Presynaptic Dynamins and Synaptic
Vesicle Recycling
The endocytic recycling of SV that compensates
SV-exocytosis is critical for keeping constant the surface
membrane area and ensuring neurotransmission efficiency
(Cardenas and Marengo 2010). Dynamins’ participation
in SV-recycling was first demonstrated in the neuromus-
cular junction of the Drosophila shibire mutant (Chen and
others 1991), which expresses a mutation in a dynamin
orthologue that affects its catalytic activity (Chen and oth-
ers 1991; Kawasaki and others 2000). Shibire is a temper-
ature-sensitive phenotype in Drosophila that results in
locomotion alterations and paralysis at nonpermissive
temperatures (>30°C) (Poodry and Edgar 1979). The lat-
ter is consequence of the inability of endocytic pits to
achieve the fission process, leading to aberrant accumula-
tion of omega-shaped structures at the presynaptic zone
and depletion of SV at nerve terminals (Koenig and Ikeda
1989). Such defect is more evident on high-frequency
stimulation, when a continuous recycling of SV is critical
for maintaining the synaptic transmission. Indeed, in teta-
nized shibire-neuromuscular junctions, synaptic currents
exhibit a constant decline until completely cease due to
depletion of the SV ready-releasable pool (RRP) (Delgado
and others 2000). These observations support the impor-
tance of the dynamins’ catalytic activity in maintaining
SV availability and have been confirmed by a consider-
able number of reports in the two last decades in both
peripheral and central synapses (Cheung and Cousin
2019; Clark and others 1997; Ferguson and others 2007;
Hayashi and others 2008; Linares-Clemente and others
2015; Lu and others 2009; Newton and others 2006;
Raimondi and others 2011; Singh and others 2018;
Tanifuji and others 2013; Yamashita and others 2005).
However, it is not entirely clear whether different dyna-
min isoforms equally participate in SV endocytic recy-
cling mechanisms or they have differential roles.
Electron microscopy studies from De Camilli’s labo-
ratory demonstrated that the knock-out (KO) of dyna-
min-1 produces accumulation of large clathrin-coated
structures at the nerve terminals of mouse primary cul-
tured cortical neurons, which associate with impairment
of the inhibitory synaptic transmission(Ferguson and oth-
ers 2007). A later report showed that the structural
4 The Neuroscientist 00(0)

changes produced by the absence of dynamin-1 are more

evident at the nerve terminals of γ-aminobutyric acid
(GABA)-ergic synapses (Hayashi and others 2008), sug-
gesting that CME is a predominant SV-recycling mecha-
nism in inhibitory neurons upon tonic activity. Since
inhibitory synapses are importantly modulated by tonic
activity, they require an efficient endocytic machinery
and likely are affected by the absence of dynamin-1 on
basal synaptic transmission (Evergren and others 2006).
Unlike that observed in GABA-ergic synapses, excitatory
transmission seems to efficiently operate on spontaneous
neuronal activity. In fact as shown by Ferguson and col-
laborators, although SV-endocytosis is severely impaired
during strong stimulation it is restored once stimulation
ceases, suggesting that dynamin 1–independent mecha-
nisms support SV recycling on tonic activity in excitatory
synapses (Ferguson and others 2007). One possibility is
that other dynamin isoforms compensate the absence of
dynamin-1. In agreement with this idea, Ferguson and
coworkers showed that the overexpression of dynamin-2
and dynamin-3 partially or completely rescue, respec-
tively, impairments in stimulus-induced SV-recycling
(Ferguson and others 2007). The generation of a dyna-
min-1/dynamin-3 double KO mouse (dKO) provided
additional evidence in favor of this idea, as dKO mice are
still able to develop efficient synapses and to recycle SV
(Raimondi and others 2011). However, some aberrant
mechanisms seem to operate in such condition. In this
sense, Lou and collaborators demonstrated that hippo-
campal neurons from dynamin 1/3 dKO mice exhibit
defective CME of SV, accumulation of arrested clathrin-
coated pits, reduction in the RRP-size and impairments in
excitatory postsynaptic currents (Lou and others 2012).
Moreover, dKO neurons express a strong facilitation of
the post-synaptic response, which is accompanied by
lower release probability in the absence of dynamin-1
and dynamin-3 (Lou and others 2012). Thus, the absence
of both dynamin-1 and dynamin-3 significantly compro-
mises the SV maintenance, even though they can be
replaceable to some extent by dynamin-2.
In 2013, experiments from Mochida’s laboratory
demonstrated that the role of different dynamin isoforms
in SV recycling depends on neuronal activity. Specific
knock-down of each classical dynamin isoform in rat
superior cervical ganglion neurons showed that the
replenishment of RRP is mediated by dynamin-1, dyna-
min-2, or dynamin-3 with different kinetics, as a func-
tion of the action potential (AP)–firing pattern. On
high-frequency stimulation, dynamin-1 mediates SV
recycling with a fast kinetics in a slow window time
greater than 50 ms (Fig. 2), while dynamin-3 operates
independent of the AP-firing pattern with slow kinetics
but in a faster time window within 20 ms of the incoming
AP (Fig. 2) (Tanifuji and others 2013). Dynamin-2
Figure 2.  Schematic diagram of the role of dynamin
superfamily proteins (DSPs) in the presynaptic mechanisms
supporting neurotransmission. In response to different
action potential (AP) firing rates, classical dynamin isoforms
are differentially recruited to mediate SV recycling. On
high-frequency stimulation, dynamin-1 (DYN1) acts with a
fast kinetics to resupply SV to the RRP (brown arrow) in a
large window time, greater than 50 ms. Independent of the
stimulation pattern, dynamin-3 (DYN3) works with slow
kinetics (orange arrow), but in a faster time window on the
AP arrival (20 ms). Dynamin-2 (DYN2) acts in an intermediate
way, responding quickly after the AP-triggering during high
frequency neuronal activity (Tanifuji and others 2013).
Mitochondria segmentation mediated by DRP1 modulates the
SV recycling by regulating mobilization from RP to RRP. GTP-
ase activity of DSPs also regulates quantal size and kinetics of
neurotransmitter release.
mediates SV-recycling in response to high frequency
neuronal stimulation, acting quickly after AP-triggering
and allowing a fast RRP resupply (Fig. 2) (Tanifuji and
others 2013). These data suggest that the three classical
dynamins are differentially required on specific patterns
of neuronal activity, being able to participate in different
endocytic mechanisms that refill the SV population at
the nerve terminals. In this regard, RRP and RP (the
reserve pool mobilized during intense neuronal activity)
(Richards and others 2003) have shown to be maintained
by different endocytosis modes. This is how, during
sparse activity, an “ultrafast endocytosis” (UFE) is trig-
gered to rapidly restore the surface area (Watanabe and
others 2013; Watanabe and others 2014). The most
understood CME appears to be triggered during mild
periods of neuronal activity (Granseth and others 2006).
Remarkably, both UFE and CME have shown to rapidly
Arriagada-Diaz et al. 5
saturate on high frequency of AP-firings (Clayton and
Cousin 2008; Granseth and others 2006; Soykan and oth-
ers 2017) making “bulk-endocytosis” relevant (Clayton
and Cousin 2008; Hayashi and others 2008; Wenzel and
others 2012; Wu and others 2014). This mechanism
relies on the formation of large endocytic structures
named “bulk endosomes,” from which SV are subse-
quently generated (Kokotos and Cousin 2015). It has
been suggested that both, UFE and CME, directly refill
the RRP (Granseth and others 2006; Watanabe and oth-
ers 2014), whereas bulk endocytosis contributes to the
SV maintenance by replenishing the RP (Cheung and
Cousin 2019). As demonstrated by Watanabe and col-
laborators, UFE depends on dynamin GTP-ase activity
and actin-cytoskeleton polymerization, and unlike CME,
it occurs adjacent to the active zones at a rate 200 times
faster than CME in hippocampal synapses (Watanabe
and others 2013). Wu and collaborators in 2014 reported
that in dynamin-1/3 dKO neurons, in which CME is sig-
nificantly impaired (Lou and others 2012), the formation
of bulk endosomes is unaffected (Wu and others 2014).
The latter suggests that bulk endocytosis requires neither
dynamin-1 nor dynamin-3, opening up the possibility
that dynamin-2 mediates this mechanism. In fact, previ-
ous reports confirmed the occurrence of dynamin-1-in-
dependent forms of bulk endocytosis in cultured
hippocampal neurons in response to intense stimulation
(Hayashi and others 2008). Since dynamin-2 quickly
orchestrates SV-recycling on high-frequency neuronal
stimulation (Tanifuji and others 2013), it is feasible that
this isoform mediates the formation of bulk endosomes.
Interestingly, it was recently demonstrated that dyna-
min-1 is also necessary for bulk endocytosis but, rather
than participate in the formation of bulk endosomes, it
appears to be important for SV generation from bulk-
endosomes (Cheung and Cousin 2019). This latter mech-
anism is compatible with a role of both, dynamin-2
mediating the formation of bulk endosomes, and dyna-
min-1 mediating the SV formation from bulk endosomes
during high frequency stimulation patterns. However,
the participation of these and other dynamin-isoforms in
SV bulk endocytosis needs to be further investigated.
The truth is that DSPs seem to be differentially
recruited, participating in specific presynaptic mecha-
nisms that depend on neuronal activity. In this regard,
Calabrese and Halpain (2015) demonstrated that changes
in the AP-firing pattern affect the presynaptic clustering
of dynamin-isoforms. Both dynamin-1 and dynamin-3,
but not dynamin-2, shown to be sensitive to the chronic
silencing of neuronal activity induced by the Na+-
voltage-dependent-channel inhibitor tetrodotoxin (TTX).
However, dynamin-1 was excluded from nerve terminals
in response to TTX, whereas dynamin-3 was accumu-
lated at the presynapses. This strongly suggests that these
three dynamin-isoforms have a differential participation
in the presynaptic homeostatic mechanisms that operate
in response to neuronal silencing (Calabrese and Halpain
2015).
An important process that has been shown to be rele-
vant in the presynaptic mechanisms of synaptic transmis-
sion is mitochondrial dynamics (Ma and others 2009).
Mitochondria are the main regulators of the cellular
metabolism, which becomes critical in neurons to support
the high energy demand during synaptic transmission and
plasticity (Mattson 2007; Todorova and Blokland 2017).
Mitochondrial dynamics includes fission, fusion, and
motility and, together with Ca2+ signaling, finely modu-
lates mitochondrial functions (Mishra and Chan 2016). A
set of DRPs regulate mitochondrial dynamics. Mitofusins
(Mfn1/2) and optic atrophy-1 (Opa1) are required for
fusion of the outer and inner mitochondrial membrane,
respectively, whereas dynamin-related protein 1 (DRP1)
and the adaptors mitochondrial fission protein 1 (Fis1),
and mitochondrial fission factor (MFF) regulate mito-
chondrial segmentation (Fig. 2) (Tilokani and others
2018). Fission/fusion imbalance severely compromises
mitochondrial function, affecting neuronal activity and
synaptic transmission (Wu and others 2019). In this
regard, DRP1 plays a pivotal role. In 2014, Berthet and
colleagues demonstrated that the deletion of DRP1 in
midbrain dopaminergic neurons leads to axonal mito-
chondria depletion, axonal degeneration and neuronal
death (Berthet and others 2014) highlighting the impor-
tance of mitochondria segmentation for neuronal mor-
phology and survival. Furthermore, DRP1 knock-out
(DRP1KO) neurons exhibit aberrant large mitochondria
and decreased levels of mitochondrial-derived ATP on
enhanced neuronal activity (Shields and others 2015).
Such defects are evident at nerve terminals but not at
soma and correlate with impaired SV-recycling and trans-
mission (Shields and others 2015). How the absence of
DRP1 could affect the resupply of SV? As demonstrated
in Drosophila neuromuscular junctions, SV-mobilization
from RP to RRP on intense neuronal activity depends on
synaptic DRP1 and on mitochondrial ATP-production
(Verstreken and others 2005). In fact, DRP1 depletion in
hippocampal neurons delays the recovery of the RRP on
high-frequency stimulation (Li and others 2013) pointing
its involvement in the presynaptic mechanisms that sup-
port synaptic transmission. Along the same line, Singh
and collaborators, reported that the presynaptic removal
of DRP1 in calyx of Held synapses, besides to impair
mitochondrial morphology, leads to a reduction in the
RRP size negatively impacting on synaptic transmission
(Singh and others 2018).
In addition to their role in the endocytic-SV recycling,
classical dynamins could have other important functions
in the regulation of neurotransmission. As reported by
6 The Neuroscientist 00(0)
Mahapatra and coworkers, the conditional knockout of
dynamin-1 (cKO) increases transmission-failures during
high-frequency stimulation in calyx of Held synapses.
However, and contrary to the expected consequence of
reducing SV recycling, cKO enhances the steady-state
neurotransmission and reduces short-term depression
during brief periods of high frequency stimulation
(Mahapatra and others 2016). As reduction in short-term-
depression was not due to modifications in the
SV-resupply rate nor to significant changes in the RRP
size (Mahapatra and others 2016) these authors suggested
the possibility that an enhanced clearance of the release
sites operate at the active zones (AZs) in the absence of
dynamin-1. Since a rapid local membrane retrieval is
important during high rates of transmitter release, fast
and massive endocytosis such as bulk endocytosis could
become predominant during brief intense stimulation
(Hayashi and others 2008; Watanabe and others 2013)
supporting the efficient clearance of the SV components
and consequently promoting transmitter release and
reducing depression (Mahapatra and others 2016). In this
regard, dynamin-1 action could be a limiting factor con-
trolling transmitter release and transmission. Indeed, oth-
ers reports also support the involvement of classical
dynamins in the mechanisms that control neurotransmit-
ter release on repetitive neuronal activity. This is how
inhibition of dynamin’s GTP-ase activity with dynasore
has been shown to accelerate the synaptic fatigue (SF)
evoked during high frequency stimulation in mouse hip-
pocampal slices (Fa and others 2014) and rat superior cer-
vical ganglion neurons (Lu and others 2009). As SF is a
form of short-term synaptic plasticity that reflects presyn-
aptic depletion of the RRP (Zucker and Regehr 2002)
these results are in agreement with a dynamin-dependent
tuning of the release of transmitters on sustained stimula-
tion. Similarly post-tetanic stimulation, another form of
short-term synaptic plasticity dependent on sustained
neurotransmitter release, is also affected by dynasore (Fa
and others 2014). Clearly, disruption of dynamins’ activ-
ity not only affects SV recycling at the presynapses but
also impacts on the efficiency of neurosecretion. In this
regard, the dynamin GTP-ase activity has been widely
implicated in the mechanisms controlling kinetics and
amount of transmitter released from endocrine cells (Min
and others 2007), neuroendocrine cells (Anantharam and
others 2011; Gonzalez-Jamett and others 2010; Gonzalez-
Jamett and others 2013a; Graham and others 2002; Tsuboi
and others 2004; Yang and others 2001) and neurons
(Wong and others 2015). The dynamins’ activity appears
to further modulate the exocytotic release of transmitters
by favoring expansion (Anantharam and others 2011;
Gonzalez-Jamett and others 2013a; Samasilp and others
2012) and reclosure (Lasic and others 2017; Tsuboi and
others 2004) of the fusion pore, a nanometric “channel”
that transiently connects the vesicular lumen with the
extracellular space allowing transmitter-output to the
synaptic cleft (Jena and others 2003). These mechanisms
appear to rely on the dynamin-actin interplay (Gonzalez-
Jamett and others 2013a; Shin and others 2018) and could
explain defects in neurotransmitter release on dynamin
disruption and sustained neuronal activity (Fa and others
2014; Mahapatra and others 2016), independent of the
SV recycling.
In summary, different DSPs are implicated in the pre-
synaptic mechanisms that support transmission and plas-
ticity of the synaptic response and in particular classical
dynamins seem to be relevant during high frequency stim-
ulations. Since intense and sustained neuronal activity is
thought to underlie plastic phenomena leading to memory
formation, dynamin’s activity is likely required for this
process (Fa and others 2014).
Postsynaptic Dynamins and
Signaling-Receptor Trafficking:
Implications in Postsynaptic
Mechanisms of Plasticity
In addition to presynaptic mechanisms, synaptic trans-
mission has a very important post-synaptic component
that determines how efficiently cells respond to neu-
rotransmitters. Besides modifications in the efficiency
with which transmitters are released from nerve termi-
nals, plasticity of the synaptic response relies on density,
type and properties of the postsynaptic receptors. Both,
excitatory (Bear and Malenka 1994; Malenka and Bear
2004) and inhibitory synapses (Gaiarsa and others 2002),
exhibit plastic mechanisms that weaken or strengthen
their efficacy. However, excitatory synaptic plasticity has
received much more attention and the postsynaptic mech-
anisms controlling its induction and expression are better
understood. Of these, long-term potentiation (LTP) and
long-term-depression (LTD) of the excitatory synaptic
transmission at the hippocampal Shaffer Collateral-
to-CA1 synapses are the most studied forms of synaptic
plasticity. Both LTP and LTD have widely shown to be
relevant for learning acquisition and memory formation
(Lee and Kirkwood 2011). Glutamate α-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid recep-
tors (AMPARs) mediate the majority of fast excitatory
synaptic transmission in the mammalian brain (Anggono
and Huganir 2012). Therefore, AMPAR trafficking into
and out of synapses is a major regulatory mechanism
underlying modifications in the efficacy of excitatory
synaptic transmission (Anggono and Huganir 2012). In
this regard, an increase in AMPAR density at the syn-
apses results in LTP (Lu and others 2001; Park and others
2004), whereas the endocytic AMPAR removal from syn-
apses leads to LTD (Carroll and others 1999; Man and
Arriagada-Diaz et al. 7

others 2000). Ca2+-dependent mechanisms determine

intracellular signaling cascades that modulate the direc-
tionality of the synaptic plasticity, for instance, by defining
the state of AMPAR phosphorylation/dephosphorylation,
which affects AMPAR trafficking, synaptic-targeting, and
function (Lee and others 2003). Remarkably, all these
mechanisms have shown to be regulated in some way by
the activity of DSPs. Among classical dynamins, isoforms
2 and 3 are most relevant in postsynapses (Okamoto and
others 2001) and seem to play major functions in AMPAR
trafficking. In 1999, Carroll and colleagues demonstrated
that overexpression of dynamin-2-K44A, a mutant unable
to bind and hydrolyze GTP, perturbs CME of AMPAR in
cultured hippocampal neurons (Carroll and others 1999).
This process occurs at specific endocytic zones (EZ)
adjacent to the postsynaptic-densities (PSDs), an elec-
tron-dense specialization of the postsynaptic membrane
that is located in close apposition to the presynaptic active
zone (Lu and others 2007a). Dynamin-2 appears to direct
AMPAR internalization in a way dependent on the activ-
ity-regulated-cytoskeleton-associated protein Arc/Ag3.1
(Chowdhury and others 2006) which in turns enhances
the dynamin-GTP-ase activity (Byers and others 2015).
From EZs, AMPAR undergo endosomal sorting processes
that can take them to a lysosomal degradation pathway
via late endosomes or back to the plasma membrane via
recycling endosomes (REs) (Ehlers 2000; Park and others
2004). On high frequencies of synaptic activity, REs
move into dendritic spines allowing a local delivery of
AMPAR (Park and others 2006). In this regard, although
some reports suggest a direct exocytosis of AMPAR into
PSDs during LTP (Gerges and others 2006; Kopec and
others 2006) most evidences suggest that postsynaptic
AMPAR insertion occurs first extrasynaptically in the
dendritic shaft, followed by a lateral diffusion from den-
dritic shaft to spines (Ashby and others 2004; Groc and
others 2004; Tardin and others 2003; Yudowski and oth-
ers 2007). In 2009, Jaskolski and collaborators reported
that the disruption of dynamin-2 GTP-ase activity with
the pharmacological agent dynasore or with the K44A
mutant inhibits the NMDAR-induced lateral diffusion of
AMPAR from dendritic shaft to spines (Jaskolski and
others 2009).The latter strongly suggests a key role of
dynamin-2 in driving a membrane drift that overrides the
topologic barrier imposed by dendritic spines and pro-
motes AMPAR delivery into PSDs (Fig. 3) As the dyna-
min GTP-ase activity is required for endosomal-recycling
pathways in different cell types (Nicoziani and others
2000; van Dam and Stoorvogel 2002), it could also regu-
late PSD-targeting of AMPAR by modulating their recy-
cling from REs. In this regard, Lu and collaborators
showed that dynamin-3, in association with the scaffold-
ing protein Homer-1, links EZs to PSDs and that such
association is critical for AMPAR-recycling (Lu and
Figure 3.  Schematic representation of the participation of
dynamin superfamily proteins (DSPs) in AMPAR-trafficking
to and from postsynaptic densities. Dynamin-2 (DYN2)
directs lateral diffusion of AMPAR from dendritic shaft to
spines in response to synaptic activity. Dynamin-3 (DYN3)
associates with Homer-1 coupling the endocytic zones
(EZs) to postsynaptic densities (PSDs) and allowing efficient
AMPAR recycling. DRP1 and DYN2 mediate mitochondrial
segmentation allowing structural and functional synaptic
plasticity.
others 2007b). As reported by these authors, experimental
approaches that disrupt the Homer-1/dynamin-3 interac-
tion induce the uncoupling of EZs from PSDs, negatively
impacting on AMPAR PSD-targeting (Fig. 3) Congruently,
EZ/PSD uncoupling impairs AMPAR-mediated spontane-
ous excitatory postsynaptic currents (Lu and others 2007b)
and stimulus-induced synaptic potentiation (Petrini and
others 2009) further supporting an important role of dyna-
min-3 in excitatory synaptic transmission and plasticity.
As occurs during presynaptic mechanisms, dynamins’
participation in AMPAR trafficking seems to depends on
neuronal activity. In this sense, constitutive AMPAR
internalization and recycling in hippocampal neurons
does not require CME or dynamin GTP-ase activity
(Fujii and others 2017; Glebov and others 2015).
Homeostatic downscaling of the synaptic response,
induced by chronic enhancement of the excitatory neuro-
nal activity, relies on the removal of AMPAR from the
plasma membrane. This mechanism neither seems to
involve the dynamin activity, but it does require actin-
cytoskeleton remodeling (Glebov and others 2015).
Notwithstanding the apparent irrelevance of dynamin’s
GTP-ase activity in constitutive AMPAR recycling,
induction of LTD by using low-frequency stimulation
8 The Neuroscientist 00(0)

Figure 4.  Pharmacological inhibition of dynamin’s GTPase activity decreases long-term potentiation (LTP). (A) Representative
diagram of the experimental setup used to obtain postsynaptic excitatory field records in hippocampal slices from 6-month-old
wild type mice. The stimulation electrode was placed on the Schaffer collaterals, while the recording electrode was placed on
stratum radiatum. Stimulation was elicited by a theta-burst (TBS) protocol to induce LTP. Field excitatory postsynaptic potentials
(fEPSP) were recorded in the Shaffer collateral-CA1 synapse during 60 minutes after TBS. Treatment with dynole 34-2 (Dyn 34-
2) and its inactive analogue dynole 31-2 (Dyn 31-2) was added 10 minutes before, during and after the LTP protocol application.
(B) Representative Dyn 31-2 (light brown) and Dyn34-2 (purple) traces of fEPSPs obtained before and after application of the
LTP protocol. (C) Note that the presence of Dyn 34-2 decreases the potentiation of the synaptic responses compared to Dyn
31-2. Dyn 31-2 (n = 19 slices from 5 mice), Dyn 34-2 (n = 11 slices from 3 mice). All data are plotted as mean ± SEM. Statistical
differences were calculated using t test,*P < 0.0001. Experimental protocols with animals were approved by the Ethics and
Animal Care Committee of Universidad de Valparaíso (BEA131-18).

pulses is significantly affected by dynamin’s inhibition
(Fujii and others 2017; Glebov and others 2015; Man
and others 2000) thus confirming dynamin’s requirement
for AMPAR internalization on specific patterns of syn-
aptic activity. Along the same line, Zheng and collabora-
tors demonstrated that AMPARs recycle in a
dynamin-independent way in the absence of synaptic
stimulation but in a CME and dynamin GTP-ase-
dependent way on chemical induction of LTP (Zheng
and others 2015). In agreement with these findings we
have confirmed in our laboratory the importance of the
dynamin’s GTP-ase activity for LTP expression in excit-
atory hippocampal synapses (Fig. 4). In our hands, treat-
ment with the dynamin inhibitor dynole 34-2 significantly
impairs LTP in wild type hippocampal slices compared
to that observed in slices treated with its inactive ana-
logue dynole 31-2 (Fig. 4; unpublished observations by
Arriagada-Díaz). These data further support the rele-
vance of the dynamin GTP-ase activity in AMPAR traf-
ficking and in the synaptic mechanisms depending on it.
Besides intrinsic dynamin’s properties allowing mem-
brane remodeling, another important regulation point
through which the dynamin GTP-ase activity could mod-
ulate AMPAR trafficking is the actin-cytoskeleton
dynamics. In fact, the dynamin activity orchestrates actin
remodeling in different experimental models by promot-
ing actin polymerization (Gonzalez-Jamett and others
2017; Gu and others 2010; Mooren and others 2009) and
Arriagada-Diaz et al. 9
by modulating actin filament stabilization (Yamada and
others 2013). Furthermore, actin dynamics constitutes an
important regulator of the intracellular trafficking
(Lanzetti 2007). At the dendritic spines, a rich actin net-
work regulates exocytosis, endocytosis and endosomal
recycling of AMPARs (Hanley 2014). Congruently, dis-
ruption of actin remodeling suppresses potentiation of
the synaptic transmission (Fukazawa and others 2003;
Kim and Lisman 1999). In addition to a functional role in
AMPAR trafficking, spine-actin has an important struc-
tural role supporting modifications in spine architecture
during induction of synaptic plasticity (Bosch and others
2014; Hanley 2014). This is how actin polymerization
associates with spine enlargement on LTP (Lin and oth-
ers 2005), while actin depolymerization associates with
spine shrinkage on LTD (Fortin and others 2012;
Okamoto and others 2009; Zhou and others 2004). Given
that classical dynamins are important regulators of the
actin dynamics (Gonzalez-Jamett and others 2017; Gu
and others 2010; Mooren and others 2009; Yamada and
others 2013) they could also affect other actin-dependent
mechanisms during structural synaptic plasticity.
Regarding structural plasticity, mitochondrial dynam-
ics is an important, although still understudied, check-
point. Mitochondria are enriched in dendrites where
“flashes” of excitable-mitochondrial events mediate
structural LTP (Fu and others 2017). Remarkably, LTP
induction prompts a burst of DRP1-mediated mitochon-
drial-segmentation, which in turns is necessary for synap-
togenesis, spine-remodeling and potentiation of the
synaptic strength (Divakaruni and others 2018). In this
regard, DRP1 overexpression, along with enhance mito-
chondrial fragmentation, increases dendritic spine den-
sity and promotes synapse formation in cultured
hippocampal neurons (Li and others 2004). Interestingly,
in addition to DRP1 activation, dynamin-2 is also required
for mitochondrial segmentation. Whilst DRP1 initiates
mitochondrial constriction facilitating dynamin-2 assem-
bly, dynamin-2 appears to mediate the last step of mito-
chondrial fission to complete division (Divakaruni and
others 2018; Lee and others 2016). This latter supports
the involvement of different DSPs in the mitochondrial-
dependent postsynaptic mechanisms that regulate excit-
atory synaptic plasticity (Fig. 4).
Finally, and besides AMPAR trafficking, dynamin-2
also participates in the endocytic recycling of N-methyl-
d-aspartate receptors (NMDARs) in excitatory glutama-
tergic synapses. As demonstrated by Montgomery and
colleagues, NMDARs are down-regulated on low-fre-
quency stimulation patterns in a way that is dependent on
dynamin-mediated endocytosis (Montgomery and others
2005). Furthermore, the endocytic recycling of other
postsynaptic receptors has also shown to be mediated by
the dynamin’s activity. For instance, dopamine-induced
D2 receptor internalization in primary-cultured striatal
neurons depends on the dynamin-2 function (Kabbani
and others 2004) suggesting its involvement in dopami-
nergic neurotransmission. Similarly, agonist- and antag-
onist-mediated internalization of serotonin 5-HT2A
receptors, a major target of antipsychotic medications,
requires dynamin GTP-ase activity (Bhatnagar and oth-
ers 2001). Moreover, endocytosis of GABAA receptors, a
major mechanism modulating experience-induced LTP
and extinction of aversive memories, also depends on the
function of dynamins (Wang and others 2017).
Thus, DSPs are critical components of the postsynap-
tic machinery, modulating most of the mechanisms that
govern synaptic transmission and plasticity.
Dynamin Implication in Synaptic
Dysfunction and Neurological
Diseases
Consistent with the role played by DSPs in the mecha-
nisms that support synaptic transmission and plasticity,
dysfunction of these proteins has been associated with an
important number of neuropathologies. Table 1 summa-
rizes some of the most relevant synaptic pathologies
implicating DSP dysfunction.
In 2007, Waterham and collaborators reported a neo-
nathal lethal case characterized by encephalopathy and
cerebral dysgenesis. This severe disorder was associated
with defects in mitochondrial and peroxisomal fission
and caused by a point mutation in the middle domain of
DRP1 (Waterham and others 2007). Other cases of
encephalopathy linked to mutations in the DRP1-
encoding gene DNM1L have been later reported (Vanstone
and others 2016; Yoon and others 2016). Some of them
also associate with seizures and refractory epilepsy
(Vanstone and others 2016). Moreover, de novo missense
mutations in the GTP-ase effector domain of DRP1 that
lead to static encephalopathy and seizures also were
recently reported (Assia Batzir and others 2019).
Classical dynamins have also been implicated in
molecular mechanisms causing epileptogenic activity.
Patients expressing de novo mutations in the DNM1 gene,
located in the middle and GTP-ase domains of dynamin-1,
suffer from seizures that start in childhood and frequently
progress to the Lennox-Gastaut syndrome, a rare and
severe kind of refractory epilepsy, accompanied with
intellectual disabilities and hypotonia (von Spiczak and
others 2017). Interestingly, seizure-like activity is sup-
pressed in shibire fly mutants (Kroll and others 2015) sug-
gesting that dynamin-dependent SV recycling could be a
potential therapeutic target in refractory epilepsy.
10
Table 1.  Synaptic Pathologies Involving Dysfunction of Dynamin Superfamily Proteins (DSPs): A Nonexhaustive List of Synaptic Disorders Linked to Deregulations in DSPs’
Activity.

DSP Synaptic Pathology Mechanism References

DRP1 Encephalopathy, microcephaly, Mutations in DNM1L gene (middle domain)/aberrant (Vanstone and others 2016; Waterham and
cerebral dysgenesis, seizures, mitochondria fragmentation others 2007; Yoon and others 2016)
refractory epilepsy
  Mutations in DNM1L gene (GTP-ase effector domain)/ (Assia Batzir and others 2019)
aberrant mitochondria fragmentation
  Alzheimer’s disease Exacerbated Aβ-induced GTP-ase activation of DRP1/ (Baek and others 2017; Kandimalla and
exacerbated mitochondrial segmentation others 2017; Yan and others 2015)
Mitofusin-2 Charcot-Marie-Tooth disease Mutations in the MFN2 gene/deregulated mitochondrial fusion (Kijima and others 2005)
Dynamin-1 Lennox-Gastaut syndrome, Mutations in DNM1 (middle and GTP-ase domains) (von Spiczak and others 2017)
refractory epilepsy, intellectual
disabilities, hypotonia
  Vascular dementia Decreased levels of dynamin-1 (Mulugeta and others 2014)
  Alzheimer’s disease Decreased levels of dynamin-1 (Kelly and others 2005; Watanabe and
others 2010)
Dynamin-2 Alzheimer’s disease Decreased levels of dynamin-2/Accumulation of membrane- (Kamagata and others 2009)
surface APP/ enhanced Aβ secretion
  Single nucleotide polymorphisms (Aidaralieva and others 2008)
  Charcot-Marie-Tooth disease Mutations in DNM2 (PH domain) (Zuchner and others 2005)
  Reduced capability to bind phospholipids (Kenniston and Lemmon 2010)
  Impaired CME/impaired microtubules instability (Claeys and others 2009; Sidiropoulos and
others 2012; Tanabe and Takei 2009)
  Impaired clathrin-independent endocytosis and membrane (Liu and others 2011)
trafficking
  Centronuclear myopathy Mutations in DNM2 (middle and PH domains) (Jeannet and others 2004)
  Cognitive impairments/learning disabilities (Bohm and others 2012; Echaniz-Laguna and
others 2007; Fischer and others 2006)
  Impaired centrosomal localization (Bitoun and others 2005)
  Impaired CME (Ali and others 2019; Bitoun and others
2009; Koutsopoulos and others 2011)
  Increased dynamin oligomerization and basal GTP-ase activity (Kenniston and Lemmon 2010; Wang and
in in vitro others 2010)
  Impaired clathrin-independent endocytosis and membrane (Liu and others 2011)
trafficking
  Impaired cytoskeletal actin dynamics and membrane (Gonzalez-Jamett and others 2017)
trafficking
Arriagada-Diaz et al. 11
A study analyzing postmortem brain tissue from
patients who had suffered from cerebrovascular insults
and developed vascular dementia (VaD) reported a cor-
relation between cognitive dysfunctions and dynamin-1
expression in affected tissues (Mulugeta and others
2014). The study included samples from patients with
VaD, VaD linked to Alzheimer’s disease (VD-AD), and
stroke without dementia (SND) who in life were sub-
jected to cognitive tests. Interestingly, bad punctuation in
these tests were highly correlated with significant
decrease in dynamin-1 levels in white matter of VaD and
VaD-AD patients, but not in SND brain patients in which
dynamin-1 levels were even increased poststroke
(Mulugeta and others 2014). These observations suggest
that dynamin-1 constitutes a protecting factor that reduces
the risk of develop dementia associated to cerebrovascu-
lar insults.
One of the most common forms of dementia in the
elderly is AD. It is characterized by progressive neuronal
deterioration and cognitive decline (Selkoe 2001). A
majority of the AD cases are sporadic forms of the disease
with late-onset (LOAD) and unknown cause (Selkoe
2001). An earlier event in LOAD is a synaptic dysfunction
caused by accumulation of soluble Aβ oligomers (Selkoe
2002). Although Aβ has multiple targets to exert its neuro-
toxicity it has been shown to accumulate in mitochondria
in AD brains (Maurer and others 2000) causing structural
and functional abnormalities such as oxidative stress, cal-
cium dyshomeostasis, impaired bioenergetics and apopto-
sis all mechanisms implicated in the Aβ-mediated
neuronal degeneration (Cha and others 2012; Lustbader
and others 2004). A considerable number of reports sug-
gest that an excessive mitochondrial segmentation linked
to DRP1 deregulation contributes to the LOAD pathogen-
esis. In this regard, Yan and collaborators showed that Aβ
triggers cytotoxic cascades that enhance the GSK3β
kinase activity promoting phosphorylation and activation
of DRP1 (Yan and others 2015). Cultured neurons express-
ing DRP1-phosphomimetics exhibit increased mitochon-
drial fragmentation and become more susceptible to
Aβ-induced apoptosis (Yan and others 2015) suggesting
that DRP1 inhibition could be a potential protecting factor
to ameliorate Aβ-toxicity. In fact, inhibition of DRP1 with
the pharmacological drug mdivi-1 manages to reduce mito-
chondrial dysfunctions and spatial memory defects in a
mouse model of AD (Baek and others 2017). In the same
line, a partial reduction of DRP1 in a mouse model of AD
that expresses hyperphosphorylated forms of the microtu-
bule-associated protein Tau reduces mitochondrial dysfunc-
tion and decreases the production of hyperphosphorylated
Tau (Kandimalla and others 2017). Certainly, these evi-
dences could support a potential role of DRP1 as a thera-
peutic target to intervene some of the pathological
mechanisms in AD.
Accumulation of Aβ in the AD context also modifies
the expression levels of classical dynamins. As demon-
strated by Kelly and colleagues in 2005, Aβ significantly
decreases dynamin-1 in hippocampal neurons, in a time
and dose-dependent way. The mechanisms include both
increased calpain-mediated degradation and down-regu-
lation of dynamins’ gene expression (Kelly and others
2005) and suggest involvement of these GTPases in the
Aβ-induced neurodegeneration. Furthermore, rats
induced to transient cerebral ischemia in combination
with synthetic Aβ peptide exhibit significant memory
defects and reduction in dynamin-1 expression levels
(Watanabe and others 2010). These changes were not
observed on induction of cerebral ischemia alone
(Watanabe and others 2010), supporting an Aβ-triggered
modification in dynamin-1 expression/degradation.
Regarding dynamin-2, its gene expression appears to
be also affected in the AD context as a significant diminu-
tion in its mRNA levels was reported in cortical tissue of
AD brains (Kamagata and others 2009). In the same work
the expression of the GTP-ase defective K44A dynamin-2
mutant led to increase Aβ secretion from SH-SY5Y
human neuroblastoma cells (Kamagata and others 2009).
Since most of the amyloid precursor protein (APP) in
these cells was observed in the surface membrane, the
authors raised the possibility that the inhibition of dyna-
min-2 GTP-ase activity impairs APP internalization
resulting in its accumulation at the plasma membrane and
enhanced Aβ secretion (Kamagata and others 2009). In
fact, something similar could happen in the AD brains in
which dynamin-2 expression is reduced. Interestingly,
single nucleotide polymorphisms in the dynamin-2-en-
coding DNM2 gene have been identified in AD patients
(Aidaralieva and others 2008). This latter study suggests
that, like other locus in the human chromosome 19, that
is, the allele ε4 of the apolipoprotein E (Borgaonkar and
others 1993), DNM2 polymorphisms could also consti-
tute a genetic risk factor in LOAD.
Mutations in DSPs have also been linked to peripheral
synapses dysfunction in the context of neuromuscular
diseases. Charcot-Marie-Tooth disease (CMT) a periph-
eral neuropathy featured by neuropathic pain, muscular
weakness, and atrophy (Claeys and others 2009) is caused
among others by mutations in genes encoding DSPs.
Mutations in the GTP-ase domain of the mitochondrial
fusion protein mitofusin-2 cause an axonal form of CMT
(Kijima and others 2005) in which degeneration of neuro-
nal axons causes muscle weakness and distal sensory loss
(Kijima and others 2005). Intermediate forms of CMT,
characterized by axonal demyelination and axonal degen-
eration are caused by mutations in the dynamin-2-encod-
ing gene DNM2 (Zuchner and others 2005). Such
mutations mainly localize in the PH domain of dyna-
min-2 affecting its capability to bind phospholipids
12 The Neuroscientist 00(0)
(Kenniston and Lemmon 2010) and impairing CME,
clathrin-independent endocytosis and membrane traffick-
ing (Liu and others 2011). Additionally, CMT-mutations
in dynamin-2 enhance the dynamin-2/microtubule asso-
ciation, impairing microtubules instability (Tanabe and
Takei 2009).
Another inherited neuromuscular disorder, centronu-
clear myopathy (CNM), is caused by mutations in the
DNM2 gene. Its clinical phenotype includes muscle
weakness, fatigability and progressive atrophy of distal
skeletal muscles (Bitoun and others 2009; Bitoun and
others 2005; Fischer and others 2006; Jeannet and others
2004). DNM2 mutations linked to CNM are mainly
located in the middle and PH domains of dynamin-2.
Most of them have shown to increase dynamin oligomer-
ization and basal GTP-ase activity in in vitro experiments
(Kenniston and Lemmon 2010; Wang and others 2010)
although it is still unclear their effect on the enzymatic
activity in a cell-context. As reported by Liu and collabo-
rators, clathrin-independent endocytosis and membrane
trafficking, but not CME, are mechanisms affected by
CNM-causing dynamin-2 mutations (Liu and others
2011). On the contrary, significant defects in CME have
been published by other authors (Ali and others 2019;
Bitoun and others 2009; Koutsopoulos and others 2011).
Moreover, as we described in 2017, CNM-causing dyna-
min-2 mutations in muscle cells impair cytoskeletal actin
remodeling and insulin-induced trafficking of the glucose
transporter GLUT4 (Gonzalez-Jamett and others 2017)
pointing out that actin dynamics and receptor trafficking
are important mechanisms affected in the CNM context.
Despite the fact that CNM is intrinsically a skeletal
muscular disorder, several clinical reports describe cogni-
tive impairments manifested as learning disabilities, lim-
ited intelligence quotient and even borderline “mental
retardation” in dynamin-2-related CNM patients (Bohm
and others 2012; Echaniz-Laguna and others 2007;
Fischer and others 2006; Jeannet and others 2004)
although the underlying mechanisms have never been
studied. Certainly, understanding signaling cascades
leading to cognitive defects in patients with CNM could
have valuable implications to better understand the role
of dynamin-2 in synaptic transmission and plasticity.
In summary, DSPs are relevant regulation points in
which converge many of the synaptic mechanisms under-
lying neurotransmission. When the activity of these pro-
teins is deregulated these mechanisms are substantially
affected, endangering synaptic health and leading to neu-
rological diseases.
Concluding Remarks
Mechanisms mediating synaptic transmission and plas-
ticity constitute the molecular basis of learning and
memory, one of the most fundamental brain functions.
As DSPs are required in a number of these mechanisms,
it can be said that their GTP-ase activity is a key factor
modulating the strength of the synaptic response and
consequently allowing memory formation. While at the
presynapses DSPs support endocytic-SV recycling and
neurotransmitter release (Fig. 2), at postsynapses, they
are critical in controlling receptor-availability at the sur-
face membranes. Particularly in excitatory glutamatergic
synapses, classical dynamins orchestrate the local traf-
ficking of AMPAR to and from PSDs (Fig. 3) supporting
excitatory synaptic plasticity. Furthermore, DRPs impli-
cated in mitochondrial dynamics (Fig. 3) are important
modulators of structural and functional synaptic plastic-
ity. It is not surprising then that on conditions affecting
expression and/or functionality of DSPs synaptic trans-
mission and plasticity are severely compromised, leading
to different pathologies of the nervous system (Table 1).
Better understanding the processes in which DSPs par-
ticipate is a major challenge in neuroscience, with a view
to using them as therapeutic targets in prevalent
synaptopathies.
Acknowledgments
We thanks Mr. Felipe Serrano and his company Illustrative-
science (www.illustrative-science.com) for constructing the
schemes presented in Figures 1, 2 and 3.
Author Contributions
All authors listed have made a substantial intellectual contribu-
tion to this work and approved it for publication.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this arti-
cle: This work was supported by ANID 22200154 (to JA-D),
Fondecyt 11180731 (to AMG-J), Fondecyt 1201342 (to AOA),
ICM-ANID ICN09-022, CINV (to AMG-J, AOA, and AMCD)
ORCID iD
Arlek M. Gonzalez-Jamett https://orcid.org/0000-0003
-2357-0260
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