The actin cytoskeleton in memory formation
Raphael Lamprecht a,b,c,
*
a
Sagol Department of Neurobiology and Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
b
Center for Gene Manipulation in the Brain, University of Haifa, Haifa, Israel
c
Center for Brain and Behavior, University of Haifa, Haifa, Israel
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Actin and memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. The roles of actin regulatory proteins in memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1. The roles of Rho GTPases signaling pathways in memory formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1.1. Rho GTPase family GAPs and GEFs in memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1.2. Rho GTPase family and memory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1.3. Rho GTPases regulated pathways in memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2. Actin capping, crosslinking, stabilizing and elongating regulatory proteins and their roles in memory formation. . . . . . . . . . . . . . . 000
3.2.1. WAVE scaffolding protein is involved in actin network formation and long-term memory . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.2. Arp2/3 in actin branching, structural plasticity and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.3. Insulin receptor tyrosine kinase substrate of 53 kDa (IRSp53) and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.4. Abi family of proteins in memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.5. Filamin, a F-actin cross linker protein, in memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.6. EPS8, an actin capping protein, is involved in memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Progress in Neurobiology xxx (2014) xxx–xxx
A R T I C L E I N F O
Article history:
Received 27 August 2013
Received in revised form 2 February 2014
Accepted 3 February 2014
Available online xxx
Keywords:
Learning and memory
Actin cytoskeleton
Actin regulatory proteins
Brain
Neurons
A B S T R A C T
The ability to efficiently store memories in the brain is a fundamental process and its impairment is
associated with multiple human mental disorders. Evidence indicates that long-term memory (LTM)
formation involves alterations of synaptic efficacy produced by modifications in neural transmission and
morphology. The actin cytoskeleton has been shown to be involved in these key neuronal processes by
subserving events such as presynaptic vesicle movement, postsynaptic glutamate receptors trafficking
and dendritic spines morphogenesis. Actin cytoskeleton dynamics and structure underlying such
cellular events can be regulated by extracellular signals through its regulatory proteins. Recent findings
show that the actin cytoskeleton and its regulatory proteins are needed for memory formation and
extinction in different organisms throughout the phyla from invertebrates such as Caenorhabditis
elegans and Drosophila to mammalians. The actin cytoskeleton and its regulatory proteins participate in
the formation of various types of memories that are subserved by different neurons and brain regions.
The actin cytoskeleton may therefore mediate between synaptic transmission during learning and longterm
cellular alterations mandatory for memory formation.
ß 2014 Elsevier Ltd. All rights reserved.
Abbreviations: ABR, active BCR-related; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; BCR, breakpoint cluster region; BLA, basolateral complex of the
amygdala; C. elegans, Caenorhabditis elegans; CNF1, cytotoxic necrotizing factor 1; CPP, (Æ)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; CTA, conditioned taste
aversion; DAB, 1,4-dideoxy-1,4-imino-D-arabinitol; DHPG, (S)-3,5-dihydroxyphenylglycine; fEPSP, field excitatory postsynaptic potential; GAPs, GTPases activating proteins;
GEFs, guanine nucleotide exchange factors; IA, inhibitory avoidance; IP3K-A, inositol 1,4,5-trisphosphate 3-kinase A; IrL, infralimbic cortex; IRSp53, insulin receptor tyrosine
kinase substrate of 53 kDa; JPK, jasplakinolide; LIMK, LIM-motif containing protein kinase; LMT, mossy fiber terminal; LTD, long-term depression; LTM, long-term memory;
LTP, long-term potentiation; MLCK, myosin light chain kinase; miRNA, microRNA; mTORC2, mammalian target of rapamycin (mTOR) complex 2; NMDA, N-methyl-Daspartate;
PAK, p21-activated kinase; PKA, protein kinase A; PKC, protein kinase C; PPF, paired-pulse facilitation; PSD, postsynaptic density; RLC, myosin regulatory light
chain; ROCK, rho-associated kinase; RP, reserve pool; RRP, readily releasable pool; STM, short-term fear memory; WAVE, Wiskott–Aldrich syndrome protein family.
* Correspondence address: Sagol Department of Neurobiology, University of Haifa, Haifa 31905, Israel. Tel.: +972 4 8288786; fax: +972 4 8288763.
E-mail address: rlamp@research.haifa.ac.il
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Contents lists available at ScienceDirect
Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio
http://dx.doi.org/10.1016/j.pneurobio.2014.02.001
0301-0082/ß 2014 Elsevier Ltd. All rights reserved.
3.2.7. Drebrin A, an actin stabilizing protein, in memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.8. Adducin, an actin filament barbed end capping protein, is needed for memory formation. . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.9. Tropomodulin, a pointed-end capping protein, is involved in memory formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.10. Spinophilin and Neubrin are actin binding proteins involved in memory formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2.11. Profilin, an actin monomer binding protein, in memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.3. The actin binding motor protein myosin in memory formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.4. MicroRNAs control of actin regulatory proteins in memory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Actin cytoskeleton in synaptic transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. Actin cytoskeleton in synaptic morphogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. The roles of actin cytoskeleton in synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.1. Synaptic plasticity and memory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2. Actin in LTP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3. Actin in LTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4. Actin regulatory proteins in synaptic plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4.1. Rho GTPases and synaptic plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4.2. Actin binding proteins and synaptic plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
7. Conclusions and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8. Actin cytoskeleton – a mediator between synaptic signaling during learning and cellular events involved in memory
formation and extinction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
9. Future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1. Introduction
Ample evidence indicates that long-term memory (LTM)
formation involves alterations of synaptic efficacy (Konorski,
1948; Hebb, 1949; Dudai, 1989; Bliss and Collingridge, 1993;
Martin et al., 2000; Tsien, 2000; Kandel, 2001; Lamprecht and
LeDoux, 2004). These changes can be mediated by modifying
synaptic release of transmitters or synaptic responses to these
transmitters. In addition, changes in neuronal morphology regulating
synaptic contacts and signal transduction near the synapse can
affect synaptic efficacy. A major challenge is to identify molecules
involved in initiating and maintaining synaptic alterations and
memory formation. Actin is a most attractive candidate to play a
central role in memory formation as it is responsive to synaptic
signaling, such as triggered during learning, and consequently may
mediate cellular events that underlie changes in synaptic efficacy,
such as synaptic transmission and morphology.
Actin cytoskeleton is involved in many pivotal cellular processes
including cellular morphogenesis, motility, division, and intracellular
transport. Actin exists in two forms in cells, either as a globular
monomer (G-actin) or following head-to-tail interaction as a
polymer to form filamentous F-actin. Actin dynamics and the
structureofF-actin networkareclosely regulatedbyactin regulatory
proteins (Luo, 2000; Dillon and Goda, 2005). These actin cytoskeleton-regulatory
proteins mediate between intrinsic and extrinsic
cellular signals and actin-dependent cellular functions. Thus, by
forming such elaborate network of actin filaments receptive to
regulatorysignals, actinmediatesa largevarietyof cellular functions
from supporting cellular morphology to providing contractile forces
needed for cellular activities including cell division and transport of
vesicles. Actin monomers and filaments are abundant in presynapses
and postsynapses and act to regulate central neuronal
processes such as changes in synaptic transmission and morphology
(Luo, 2002; Dillon and Goda, 2005; Cingolani and Goda, 2008;
Nelson et al., 2013). Changes in synaptic transmission and neuronal
morphology are involved in the process of memory formation
(Lamprecht and LeDoux, 2004).
This review is focused on the roles of the actin cytoskeleton in
memory formation. As mentioned above, actin is involved in
neuronal transmission and morphogenesis and in synaptic
plasticity (Luo, 2002; Dillon and Goda, 2005; Cingolani and Goda,
2008) neuronal processes that have been shown to be involved in
memory formation. These findings beg the questions: is the actin
cytoskeleton needed for long-term memory formation? If so,
which cellular mechanisms are modulated by the actin cytoskeleton
and how they subserve memory formation?
2. Actin and memory formation
Studies have shown that the actin cytoskeleton is needed for
memory formation. Actin was shown to be needed for the creation of
memory in animals across the phyla and in various behavioral
paradigms mediated by different neurons and brain regions.
Interfering with actin rearrangements (e.g. inhibition of actin
polymerization) at a particular time window during learning or
afterwards impairs normal memory formation. Useful chemicals for
interfering with the actin cytoskeleton rearrangements are latrunculin
A that forms a nonpolymerizable 1:1 complex with G-actin to
inhibit actin polymerization, cytochalasin D that caps the growing
end of actin filaments and thus changes the polymerization and
depolymerization rates of F-actin and phalloidin that binds to Factin
preventing its depolymerization and stabilizes it. For example,
local application of actinpolymerization inhibitors cytochalasin D or
latrunculin A into the mushroom bodies of the honeybee 1 h before
induction of long-term memory enhanced associative olfactory
memory (Ganeshina et al., 2012). In rats, actin cytoskeleton is
needed for spatial memory as intrahippocampal infusion of actin
rearrangement inhibitor, latrunculin A, 15 min prior to initiation of
the object placement task impaired object placement memory
(Nelson et al., 2012). Actin cytoskeleton is also needed for aversive
memories in rats as infusion of cytochalasin D or latrunculin A 4 h
after conditioned taste aversion (CTA) into the insular cortex or
prelimbic cortex, but not into the basolateral nucleus of the
amygdala, impaired CTA LTM tested 72 h post-conditioning (Bi et al.,
2010). Bilateral microinjection of latrunculin A into the amygdala
10 min before pairing with morphine withdrawal and infusion of
latrunculin A into the dorsal hippocampus immediately afterpairing
significantly impaired conditioned place aversion (CPA) memory
(Hou et al., 2009). Methamphetamine-associated memory in
amygdala is disrupted by actin depolymerization (Young et al.,
2014). Actin rearrangements were also shown to be involved in fear
memory formation. Intra-hippocampal infusion of actin cytoskeleton
assembly inhibitors (latrunculin A or cytochalasin D) in mouse
impaired the consolidation of contextual fear memory (Fischer et al.,
2004) and microinfusion of cytochalasin D into rat LA immediately
before fear conditioning training interfered with the formation of
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long-term fear memory (LTM) but not short-term fear memory
(STM; Mantzur et al., 2009). Furthermore, microinfusion of
cytochalasin D into rat LA immediately after fear conditioning
dampened LTM. Cytochalasin D had no effect on fear conditioning
memory retrieval when injected immediately before LTM test.
Rehberg et al. (2010) showed that auditory cued but not contextual
fear memory was disrupted, when the actin depolymerization
inhibitor phalloidin was injected into basolateral complex of the
amygdala (BLA) 6 h after conditioning. Re-consolidation of memory
is also dependent on regulation of actin polymerization (Rehberg
et al., 2010).
Actin cytoskeleton is also involved in memory extinction.
Extinction is the decline in the frequency or intensity of a
conditioned response when the stimulus that served as the
conditioning stimulus is presented in the absence of the
reinforcement (Pavlov, 1927). It does not reflect forgetting,
but a process of relearning of a new association of the
conditioned stimulus with the absence of the original reinforcer
(e.g. Bouton, 1994; Rescorla, 1996). Conditioned fear responses
to a tone or context paired with footshock rapidly extinguish
when the tone or context are presented in the absence of the
shock. Microinjection of latrunculin A or cytochalasin D into the
hippocampus impaired the extinction of contextual fear memory
(Fischer et al., 2004). Microinjection of cytochalasin D into the
BLA or CA1 was shown to impair the return of fear after
reconditioning at the last extinction session showing that actin
polymerization is also required for reconditioning (Motanis and
Maroun, 2012).
In summary, the aforementioned studies indicate that actin
cytoskeleton is needed for memory formation and extinction in
various organisms across the phyla. Actin cytoskeletal is needed for
the formation of different types of memories and in different brain
areas. It is therefore possible that similar cellular events, subserved
by the actin cytoskeleton, occur following different learning
paradigms and are needed for memory formation. Such events
could include alteration in neuronal morphology such as changes
in dendritic spines (referred as spines in the review below) or
alteration in synaptic efficacy such as changes in amount of
postsynaptic glutamate receptors known to be mediated by actin
cytoskeleton (see below, table and Fig. 2). Importantly, studies
provide evidence that interfering with actin dynamics that affect
memory formation has no effect on normal synaptic transmission.
For example, actin dynamics inhibitor in LA affects LTM formation
but not fear memory retrieval (Mantzur et al., 2009) which
requires synaptic transmission (e.g. Muller et al., 1997).
3. The roles of actin regulatory proteins in memory
How does neuronal activation during learning lead to alterations
in actin cytoskeleton required for memory formation? Actin
cytoskeleton polymerization, depolymerization and branching are
closely controlled by regulatory proteins (Luo, 2000). Other actinmediated
function such as intracellular transport and contractility
are also mediated by actin-binding proteins (Kamm and Stull, 2001;
Somlyo and Somlyo, 2003). These regulatory proteins (Fig.. 1) can
mediate actin involvement in memory formation as they are
Fig. 1. Actincytoskeletonand itsregulatory proteinsareinvolvedinmemory formation. Evidence showsthatmemory formationdependsonthe activationofglutamatereceptors,
calcium channels, receptors tyrosine kinases such as Eph receptors and adhesion molecules. Activation of these receptors and channels during or after learning may lead to
regulation of intracellular signaling cascades that affect actin dynamics and structure and consequently cellular processes such as neuronal morphogenesis. Among these
regulatedmolecules are the Rho, Rac, andCdc42 GTPases andtheir effectors and actin-binding proteinssuch as profilin,Arp2/3, Eps8, Adducin, drebrin, Filamin andTropomodulin
shown to regulate actin polymerization, elongation, stabilization and branching. Of note is the fact that while actin regulatory protein activation may lead to regulation of similar
effectors their effects on cellular function may be different. This may be due to different spatiotemporal regulation of these regulatory proteins. This figure illustrates the tight
regulation of actin cytoskeleton needed for synaptic plasticity and memory formation. AMPAR – a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CaM – calmodulin;
IRSp53 – insulin receptor tyrosine kinase substrate of 53 kDa; LIMK – LIM-kinase; MLC – myosin light chain; MLCK – myosin light chain kinase; MLCP – myosin light chain
phosphatase; NMDAR, N-methyl-D-aspartate receptor; PAK, p21-activated kinase; ROCK – rho-associated kinase; WAVE – Wiskott–Aldrich syndrome protein family.
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functionally linked with synaptic receptors that participate in
memory formation such as the glutamate receptors, Eph receptors,
and adhesion molecules such as cadherin (Gerlai et al., 1999;
Rodrigues et al., 2004; Schrick et al., 2007; Maguschak and Ressler,
2008; Savelieva et al., 2008). For example, actin dynamics in spines
are inhibited by activation of either a-amino-3-hydroxy-5-methyl-
4-isoxazole propionic acid (AMPA) or N-methyl-D-aspartate
(NMDA) glutamate receptors (Fischer et al., 2000). Moreover,
activation of either receptor inhibited actin-based protrusive
activity from spine head. In addition, several actin regulatory
proteins,such as members of the Rho GTPase family, are activatedby
glutamate receptor to regulate neuronal morphogenesis. For
example, studies are available suggesting that RhoA mediates the
promotion of normal dendritic arbor development by NMDA
receptor activation (Li et al., 2000), and recruitment and activation
of RhoA underlies spines morphology in a glutamate receptordependent
manner (Schubert et al., 2006). Two-photon glutamate
uncaging leads to long-term volume increase of single spine and to
rapid activation of RhoA and Cdc42 in stimulated spine (Murakoshi
et al., 2011). Moreover, NMDA or its downstream signaling
pathways stimulation may lead to regulation of Rho or Rac GTPases
activity (e.g., Tejada-Simon et al., 2006; Nakazawa et al., 2008;
Saneyoshi et al., 2008). Eph receptors are also regulators of the Rho/
Rac/Cdc42 GTPase proteins and affect actin dynamics and neuronal
morphology (Shamah et al., 2001; Irie and Yamaguchi, 2002; Penzes
et al., 2003; Egea and Klein, 2007; Klein, 2009). Adhesion molecules
may regulate Rho/Rac/Cdc42 GTPase proteins to affect actin
cytoskeleton (e.g. Bruse´s, 2006). Thus, synaptic molecules such as
receptors and adhesion molecules activated during learning may
affect actin-regulatory proteins leading to changes in actin
cytoskeleton that subserve memory formation. The following
sections will describe the roles of actin regulatory proteins in
memory formation.
3.1. The roles of Rho GTPases signaling pathways in memory
formation
3.1.1. Rho GTPase family GAPs and GEFs in memory
The Rho GTPase proteins (Rho/Rac/Cdc42) have been shown be
activated by extraneuronal stimuli such as neurotransmission and
adhesion (e.g. Luo, 2002; Dillon and Goda, 2005; Newey et al.,
2005; Heasman and Ridley, 2008; Hall and Lalli, 2010; Tolias et al.,
2011). Activation of Rho GTPases can alter actin cytoskeleton
dynamics and structure (e.g. Luo, 2002; Dillon and Goda, 2005;
Newey et al., 2005; Heasman and Ridley, 2008; Hall and Lalli,
2010). These molecules are also involved in memory formation
(see below). Proteins that transduce signals from extra and
intracellular signals to regulate the Rho GTPAses activity are the
Guanine nucleotide exchange factors (GEFs) that activate monomeric
GTPases by stimulating the release of guanosine diphosphate
(GDP) to allow binding of guanosine triphosphate (GTP) and
the Rho GTPase family activating proteins (GAPs) that bind to
activated G proteins and stimulate their GTPase activity, with the
result of terminating their signaling.
RhoGAP and RhoGEF families were shown to be activated by
extracellular signaling including neurotransmitters and adhesion
molecules in neurons. For example, NMDA receptor activation in
pyramidal neurons leads to phosphorylation of the guaninenucleotide
exchange factor (GEF) kalirin-7, regulating its GEF
activity (Xie et al., 2007). Kalirin could also be regulated by
receptors that are intimately involved in neuronal morphogenesis
such as EphB2 receptors (Penzes et al., 2003). The activation of the
EphB receptor induces translocation of kalirin to synapses and
activation of Rac1 and its effector p21-activated kinase (PAK). The
activation of RhoGAPs and RhoGEFs may lead to alteration in
neuronal processes such as morphogenesis. For example, kalirin
expression and spine localization are required for activitydependent
spine enlargement and enhancement of AMPARmediated
synaptic transmission (Xie et al., 2007). Thus, RhoGAPs
and RhoGEFs could serve as cellular signaling mediators that
couple extracellular stimuli during learning to Rho GTPases and
actin cytoskeleton rearrangements subserving neuronal functions
needed for memory formation. Studies below provide evidence
that RhoGAP and RhoGEF are involved in memory formation.
The p190 RhoGAP is implicated in memory formation. P190
RhoGAP is a major substrate of the tyrosine kinase Src in the brain,
and its phosphorylation by this kinase facilitates its interaction with
p120 RasGAP and inhibits its RhoA-GAP and GTP-binding activities
(Roof et al., 2000). P190 RhoGAP is intimately involved in brain
development. P190 RhoGAP mutant mice exhibit neural developmental
defects such as abnormalities in forebrain hemisphere fusion
and neural tube closure and aberrations in axon outgrowth,
guidance and fasciculation (Brouns et al., 2000; Brouns et al.,
2001). P190 RhoGAP knockout in Drosophila causes retraction of
axonal branches (Billuart et al., 2001). Importantly, evidence is
available that p190 RhoGAP is involved in mediating actin
reorganization. Specifically, in p190 RhoGAP mutant mice, polymerized
actin accumulates extensively in cells of the neural tube
floor, suggesting that p190 RhoGAP plays a role in regulating actin
assembly (Brouns et al., 2000). P190 RhoGAP is involved in fear
memory formation. Following fear conditioning, the tyrosine
phosphorylated p190 RhoGAP becomes associated with a molecular
complex in LA that includes the adaptor molecule GRB2 (Lamprecht
et al., 2002). In addition, studies have shown that p190 RhoGAP may
mediate Ptprz protein activities needed for memory formation.
Ptprz is a receptor-type protein tyrosine phosphatase expressed in
thebrain(Nishiwakietal.,1998).Ptprzselectivelydephosphorylates
pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at
Y1105 controls p190 RhoGAP activity in vivo (Tamura et al., 2006).
Ptprz-deficient mice exhibit an age-dependent impairment of
Morris water maze learning and impairments in contextual fear
memory (Niisato et al., 2005; Tamura et al., 2006). Interestingly the
authors found that p190 RhoGAP phosphorylation is decreased 1 h
after the conditioning in the hippocampus of wild-type mice, but not
of Ptprz-deficient mice.
Oligophrenin1 is a RhoGAP protein that inhibits RhoA, Rac1, and
Cdc42 (Fauchereau et al., 2003; Govek et al., 2004). Oligophrenin-1
is expressed in the developing and adult brain, and present in
neurons and glial cells where it colocalizes with F-actin
(Fauchereau et al., 2003). In neurons oligophrenin-1 is found in
pre- and post-synapse. Loss of oligophrenin-1 in knockout mice
leads to immaturity of spines in the adult CA1 hippocampus
(Khelfaoui et al., 2007). Long-term potentiation (LTP) and mGluRdependant
long-term depression are normal in the CA1 hippocampal
area of oligophrenin-1 KO, whereas paired-pulse facilitation
is reduced suggesting alteration in presynaptic processes
involved in the release of neurotransmitters. Oligophrenin-1 KO
mice are impaired in Morris water maze spatial learning (Khelfaoui
et al., 2007).
Breakpoint cluster region (BCR) and active BCR-related (ABR)
show RacGAP activities both in vitro and in vivo (Diekmann et al.,
1991; Heisterkamp et al., 1993; Tan et al., 1993; Chuang et al.,
1995; Voncken et al., 1995; Kaartinen et al., 2001; Cho et al., 2007).
BCR or ABR KO induces a small increase in spine density without
affecting excitatory synaptic transmission (Oh et al., 2010). Long
term potentiation maintenance, but not induction, is impaired in
BCRÀ/À or ABRÀ/À mice whereas long-term depression is normal
(Oh et al., 2010). The BCRÀ/À and ABRÀ/À mice are impaired in
Morris water maze and long-term object recognition memory (Oh
et al., 2010).
The RacGAP, WRP, is thought to regulate central functions of
synapse development and function and may be linked to mental
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retardation in humans (Endris et al., 2002). The loss of WRP in vivo
and in vitro leads to reduction in spines density. In vivo the loss is
primarily of mushroom-shaped spines (Carlson et al., 2011). The
loss of WRP led to impairments in long-term novel object
recognition, water maze and passive avoidance memory (Carlson
et al., 2011).
KALRN gene encodes for the kalirin Rac-GEF and can produce
functionally distinct isoforms in a tissue-specific and developmentally
regulated manner (McPherson et al., 2004). It was shown that
kalirin can activate Rac1 and alter actin dynamics (e.g. Penzes et al.,
2000). KALRN-deficient mice exhibit reduced cortical glutamatergic
transmission, show brain region-dependent reductions in spine
density and impairment in memory as assessed by Morris water
maze and spontaneous alternation task in the Y-maze paradigm
(Cahill et al., 2009; Vanleeuwen and Penzes, 2012). Kalirin-7 was
shown to be involved in neuronal morphogenesis (Penzes et al.,
2001).Knockoutof Kalirin-7inmiceleadstodecreased hippocampal
spine density (Ma et al., 2008). Furthermore, in the KO mice early
stages of cortical excitatory synaptic development proceeded
normally with decreased excitatory synapses apparent after 21
days. These mice were impaired in short- and long-term passive
avoidance conditioning and exhibited normal learning in radial arm
maze and object recognition tasks. Thus, regulation of synaptic
transmission and spines morphology by kalirin may be important
for cognition. Another study shows that Kalirin KO mice were
impaired in fear responses to the context when tested 45 min, 24 h
and 48 h after contextual fear conditioning indicating an impaired
ability of animals to acquire and consolidate new contextual fear
memories (Xie et al., 2011). Mice were also impaired in cued fear
conditioning where they associated sound with footshock. Mice
were impaired in the 45 min and test 24 h tests but not in the 48 h
test indicating that the mice are impaired in acquisition and early
consolidation but not in latent onset of consolidation of cued fear
conditioning memory.
Tiam1, a RacGEF, may also be involved in memory formation as
phosphorylation of TrkB receptor, needed for memory formation, is
required for its interaction with Tiam1 and with Rac1 activation
during activity dependent spine remodeling (Lai et al., 2012).
Tiam1 also binds to and functions downstream of the NMDA
receptor (Tolias et al., 2005).
3.1.2. Rho GTPase family and memory
As described above Rho GTPase family GAPs and GEFs are
involved in memory formation. These proteins regulate Rho
GTPases and the question that arises is whether Rho GTPases
are involved in memory formation? Indeed, several studies have
provided compelling evidence for such a role. In Drosophila
inhibition of Rac GTPase activity leads to slower decay of Pavlovian
olfactory aversive conditioning memory, prolonging it from a few
hours to more than one day, and to blockade of interferenceinduced
forgetting. Conversely, increase in Rac GTPase activity in
mushroom body neurons accelerates memory decay (Shuai et al.,
2010). Rac activity triggers downstream activation of PAK and
LIMK (LIM kinase), which in turn phosphorylates cofilin and
inhibits its actin depolymerization activity (see below and Arber
et al., 1998; Yang et al., 1998; Edwards et al., 1999). In Drosophila,
hyperactivation of cofilin gives rise to the same phenotype as seen
with Rac inhibition (Shuai et al., 2010). Thus, hyperactivation of
cofilin following Rac inhibition may facilitate actin depolymerization
and memory decay. Expression of a dominant-negative form
of Drosophila Rac1, Drac1(N17) throughout the adult brain
enhances the learning of Pavlovian trace conditioning of odor
avoidance response compared with the two parental controls but
leaves simultaneous conditioning unaffected (Shuai et al., 2011).
In rats microinjections of the Rac GTPase inhibitor NSC23766
into the nucleus accumbens (NAc) core but not shell, basolateral
(BLA), or central amygdala (CeA) after each cocaine-conditioning
session inhibited the consolidation of cocaine-induced long-term
conditioned place preference (CPP) memory (Ding et al., 2013).
Microinjection of NSC23766 into the BLA but not CeA, NAc core, or
NAc shell disrupted the reconsolidation of cocaine-induced CPP.
Diana et al. (2007) have shown that the cytotoxic necrotizing
factor 1 (CNF1) injected intracerebroventricular (i.c.v.) leads to
activation of cerebral RhoA and Rac1, to rearrangement of cerebral
actin cytoskeleton as shown by an increase in F-actin and to
enhanced hippocampal neurotransmission and synaptic plasticity.
Microinjection of CNF1 led to enhancement of long-term contextual
fear conditioning memory as tested 1 and 10 days after training.
Cuedfear conditioning toatonewas not different1 dayaftertraining
but was enhanced 10 days afterwards. Mice showed an improvement
of Morris water maze performance. The effects persisted for
weeks. In addition, CNF1 intracerebroventricularly improved object
recognition memory in both C57BL/6J and CD1 mice (Borrelli et al.,
2013). The improvement is long lasting and was observed weeks
after treatment. CNF1 also enhanced working memory for object
location/discrimination in mice (De Viti et al., 2010).
Postnatal conditional knockout of Rac1 leads to fewer synapses,
but existing spines are larger than those in control hippocampal
neurons (Haditsch et al., 2009). Loss of Rac1 impaired LTP in both
CA1 and dentate gyrus. Rac1 mutants are impaired in Morris water
maze hippocampus-dependent spatial learning but not in longterm
memory. The Rac1 deficient mice are impaired in working/
episodic-like memory as tested in the ‘‘delayed matching-toplace’’
(DMP) version of the Morris water maze.
The Rac3 isoform is involved in behavioral flexibility. Rac3
knockout mice do not show defects in spatial reference memory
assessed by water maze task but are different from wild type mice
in the reversal phase showing difficulties to locate the new
platform position indicating on a reduced behavioral flexibility to
novel situations (Corbetta et al., 2008).
Rac-1 pathway is also involved in memory extinction. Mice
injected with a Rac-1 inhibitor (NSC23760) intracerebroventricular
immediately after each day of the contextual fear memory
extinction days 1–3 showed facilitated extinction. Similar results
were obtained by intrahippocampal injections (Sananbenesi et al.,
2007).
Rac GTPase can be engaged in various intracellular pathways to
affect memory. For example, in a recent study it was shown that
Rictor (rapamycin-insensitive companion of mTOR) deficient mice
are impaired in both long-term memory (LTM) and the late phase
of hippocampal long-term potentiation (L-LTP) and that Rac1GTPase
signaling and actin may be involved in mediating this
process (Huang et al., 2013). This study revealed that conditional
deletion of Rictor in the postnatal murine forebrain greatly reduced
mammalian target of rapamycin (mTOR) complex 2 (mTORC2)
activity and impaired both long-term memory (LTM) and
hippocampal L-LTP (Huang et al., 2013). Rictor fb-KO mice were
impaired in long- but not short-term contextual and auditory fear
memory. Rictor fb-KO mice were also impaired in spatial LTM as
tested in the Morris water maze, where mice use visual cues to find
a hidden platform. Several observations suggested that the
phenotype observed in the Rictor KO mice engages alterations
in actin polymerization. First, spine density in CA1 pyramidal
neurons was reduced in Rictor fb-KO mice. Second, Rac1 GTPase
activity and the phosphorylation of PAK and cofilin were reduced
in CA1 neurons of Rictor fb-KO mice. Third, the ratio of
polymerized F-actin to G-actin monomers, which indicates on
the balance between actin polymerization and depolymerization,
was reduced in CA1 of Rictor fb-KO mice. Fourth, microinjection of
jasplakinolide (JPK), a compound which directly promotes actin
polymerization, into the CA1 region improved contextual fear LTM
in Rictor fb-KO mice indicating that actin dynamics account at least
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to some extent for the impairment of LTM in these mice. JPK also
enhanced contextual fear LTM in wt mice when the mice were
trained with a weak conditioning protocol.
Another example of Rac GTPase possible involvement in
memory formation is through its interaction with the inositol
1,4,5-trisphosphate 3-kinase A (IP3K-A) pathway. Neural activation
leads to binding of IP3K-A, a brain-specific molecule that is
enriched in spines (Mailleux et al., 1991), to activated Rac1 and to
its recruitment to the actin cytoskeleton in the postsynaptic area
leading to spine formation through actin dynamics downstream of
Rac signaling (Kim et al., 2009a). IP3K-A knock-out mice exhibited
impairments in synaptic accumulation of PAK1 caused by LTPinducing
stimulation and reduction in the reorganization of actin
cytoskeleton in dentate gyrus synapses. In addition, IP3K-A knockout
mice showed deficits in synaptic plasticity in perforant path
and in spatial memory using the radial arm maze test. Translocation
of Rac and its activation was also shown to be increased in the
hippocampus following contextual fear conditioning in mice in an
NMDA-depended manner (Martinez et al., 2007).
Cumulatively, the above observations show that RhoGAP and
RhoGEF families and their downstream affectors the Rho GTPase
family of proteins, that affect the actin cytoskeleton, are involve in
memory formation. The findings that the same protein (e.g. Kalirin)
affects different memories suggests that similar cellular changes
occur in different brain regions and following various types of
learning. The observation that different proteins, sometime with
opposite effects (e.g. RacGAP and RacGEF in water maze) are
involved in the same memory formation is not necessarily
contradictory as the proteins may be activated in different
microcellular regions and time points. Regular genetic and
pharmacological manipulations have an insufficient spatiotemporal
resolution to be able to differentiate between such events.
3.1.3. Rho GTPases regulated pathways in memory
Rho GTPase family exerts their effects on actin dynamics by
regulating downstream effectors (Luo, 2000; Fig.. 1). A major direct
effector of Rho GTPase is the Rho-associated kinase (ROCK; Riento
and Ridley, 2003; Amano et al., 2010). ROCK phosphorylates a
number of proteins involved in regulating actin cytoskeleton
including myosin light chain phosphatase and LIMK. Phosphorylation
of myosin light chain or of myosin light chain phosphatase
has an immediate impact on actin contractility (Kamm and Stull,
2001; Somlyo and Somlyo, 2003). LIMK exerts its effect on actin
polymerization by phosphorylating and inactivating the actin
depolymerization factor (ADF)/cofilin (Arber et al., 1998; Yang
et al., 1998; Sumi et al., 1999). Activation of LIMK by ROCK has been
associated with phosphoregulation of ADF/cofilin (Maekawa et al.,
1999). Cofilin plays an essential role in regulating actin filament
dynamics and reorganization also by stimulating the severance
and depolymerization of actin filaments (Bamburg and Bernstein,
2008). Rac GTPase and Cdc42 activate p21 activated kinase1
(PAK1), which in turn activates LIMK (Edwards et al., 1999) and
therefore can affect actin dynamics (Bokoch, 2003). The following
sections address the roles of Rho GTPases downstream effectors in
memory formation and extinction.
3.1.3.1. Rho-associated kinase (ROCK) and memory. Rho-associated
kinase was shown to be involved in memory formation. Inhibition
of ROCK in lateral amygdala (LA) impaired the formation of longbut
not short-term fear memory formation (Lamprecht et al.,
2002). Intra-LA infusions of the ROCK inhibitor Y-27632 impaired
fear conditioning-induced expression of pre- and post-synaptic
proteins GluR1, synapsin and synaptophysin in the LA (Ota et al.,
2010). The investigators suggest that changes in the actin
cytoskeleton induced by the Rho/ROCK signaling pathway may
be responsible for the pre- and postsynaptic changes observed at
the LA synapse following fear conditioning. ROCK inhibition prior
to fear conditioning training attenuated fear memory and neuroxin
splicing repressions in hippocampus (Rozic et al., 2011). Microinjection
of ROCK inhibitor into the gustatory cortex impaired longterm
CTA memory formation but not retrieval, relearning or
incidental taste learning (Sweetat et al., 2012). Post training
intrahippocampal infusion of Y-27632 impairs long-term Morris
water maze memory (Dash et al., 2004).
3.1.3.2. p21 activated kinase (PAK) and memory formation and
extinction. PAK is involved in neuronal morphogenesis and
memory formation and extinction. Cortical neurons in forebrainspecific
dnPAK transgenic mice exhibited fewer spines and an
increased proportion of larger synapses (Hayashi et al., 2004).
These mice were impaired in bidirectional synaptic modifiability
(enhanced LTP and reduced LTD) in the cortex. The mutant mice
were normal in acquisition of Morris water maze but impaired in
this task when tested 21 days (but not 1 day) after training
indicating that consolidation/retention of this memory is impaired
in the transgenic mice. Similarly, animals were normal in shortterm
contextual fear conditioning memory but impaired in longterm
memory when compared to controls. Pak5À/À Pak6À/À
double KO acquired the correct avoidance response in the active
avoidance component of the T-maze at a much slower rate than the
wild type mice and performed more poorly in most of the sessions
(Nekrasova et al., 2008). Pak5À/À;Pak6À/À mice performed worse
than wild type mice in passive avoidance task. Anxiety levels are
normal in the Pak5À/À;Pak6À/À mice but they suffer from deficits
in locomotor activity and strength. Although some behavioral
differences were seen in the Pak5 and Pak6 single KO mice, the
double KO mice showed the greatest changes in locomotion and
learning and memory (Furnari et al., 2013).
PAK-1 is also involved in memory extinction. Mice that were
trained for contextual fear conditioning and were microinjected
24 h later with HSV–dnPAK-1 into the hippocampus showed a
significant impairment in extinction when compared with HSVGFP
control group (Sananbenesi et al., 2007). These data indicate
that inhibition of PAK-1 activity impairs extinction.
3.1.3.3. LIMK and memory. ROCK and PAK can regulate actin
cytoskeleton via signaling molecules such as LIMK that affects
actin dynamics. The normal distribution of actin in hippocampal
neurons (showing higher level in the spines compared to
dendrites) was disrupted in LIMK-1 knockout neurons (the spine
intensity of actin staining is weak and not significantly higher than
that of dendritic areas) indicating that LIMK-1 is critical for a high
level of expression of actin filaments in the spines. Furthermore, in
LIMK-1 KO neurons actin filaments accumulate abnormally along
the dendrites (Meng et al., 2002). The knockout mice exhibited
significant abnormalities in spine and axonal morphology. LTP
induced by tetanic stimulations of 5 or 10 Hz in mice was impaired
in the LIMK knockout slices but LTP induced by 50 or 100 Hz
stimulation was clearly enhanced in the KO mice (Meng et al.,
2002). The LIMK-1 knockout mice also showed enhanced cued fear
conditioning LTM. These mice were tested also in spatial memory
task the Morris water maze showing significant impairment in
locating a submerged platform position when the platform was
moved to the opposite quadrant during the learning reversal phase
indicating of impairment in some aspects of spatial memory
formation. These results indicate that the regulation of actin
polymerization by the LIMK pathway is essential for normal fear
and spatial memory formation.
3.1.3.4. Cofilin and memory. The LIMK effector cofilin regulates
actin dynamics and is involved in memory formation. Mice in
which n-cofilin was removed from principal neurons postnatally
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(N-cofflx/flx,CaMKII-cre) were tested cellularly and behaviorally. A
50–60% increase in the F/G-actin ratio was detected in cortex and
hippocampus synaptosomes of mutant mice compared to controls
showing that n-cofilin is critical to maintain the equilibrium of
synaptic F-actin and G-actin. The density of spines in CA1
pyramidal neurons of n-cofflx/flx,CaMKII-cre,Thy1-GFP mice was
increased compared to control mice. The number of mushroomshaped
spines was higher in mutant mice and spine heads were
also larger, but the number of filopodia-like spines was not altered.
N-cofilin is shown to be important for synaptic plasticity (L-LTP or
LTD) and for AMPAR mobility. N-cofflx/flx,CaMKII-cre mice are
impaired in Morris water maze learning and in contextual and
cued fear learning (Rust et al., 2010). N-cofflx/flx,CaMKII-cre mice
performed worse when compared to controls in conditioned place
preference reward learning. Short-term working memory and
exploratory learning are shown to be n-cofilin independent.
Cofilin phosphorylation is altered by behavior. Rats trained in
inhibitory avoidance (IA) exhibit an increase in phospho-cofilin (pcofilin)
20 h after training in the hippocampus. This increase is
dependent on astrocytic glycogenolysis as it is blocked by 1,4dideoxy-1,4-imino-D-arabinitol
(DAB), an inhibitor of glycogen
phosphorylation, that also blocked long-term, but not short-term,
IA memory (Suzuki et al., 2011). In another study rats were allowed
to explore a compartmentalized environment for 30 min. Rats that
explored the environment had 30% more spines with dense
phosphorylated cofilin in hippocampal CA1 than did rats in the
home-cage group. The increase in p-cofilin containing spines and
behavioral evidence for memory of the explored environment
were both eliminated by the NMDA receptor antagonist (Æ)-3-(2carboxypiperazin-4-yl)propyl-1-phosphonic
acid (CPP) (Fedulov
et al., 2007). Object placement training resulted in increased
hippocampal levels of p-cofilin (Nelson et al., 2012). Another study
has shown that b-arrestin-2 plays a critical role in NMDA-induced
changes of spines and synapses via translocation of active cofilin to
spines (Pontrello et al., 2012). b-arrestin-2 KO are impaired in water
maze learning.
Cofilin is also involved in memory extinction. The extinction of
conditioned taste aversive (CTA) memory led to temporally
enhanced ADF/cofilin activity in rat infralimbic cortex (IrL; Wang
et al., 2013). Elevation of ADF/cofilin activity in the IrL facilitated
CTA memory extinction whereas inhibition of ADF/cofilin activity
impaired memory extinction. Cofilin activity was also needed for
the regulation of AMPA receptor trafficking to the synapse. It was
also shown that extinction training decreased LIMK1 activity while
increasing Slingshot (SSH1) activity. Cofilin is mainly phosphorylated
by LIMKs and dephosphorylated by Slingshot (SSH)
phosphatase (Van Troys et al., 2008).
Taken together, the above observations show that disrupting
proteins activities within the pathways from the synapse to cofilin
(via ROCK or PAK) can affect actin cytoskeleton dynamics and
memory formation and extinction. Thus, cumulatively these
results implicate these pathways in memory formation (Fig.. 1).
3.2. Actin capping, crosslinking, stabilizing and elongating regulatory
proteins and their roles in memory formation
3.2.1. WAVE scaffolding protein is involved in actin network
formation and long-term memory
The WAVE isoforms (WAVE-1, WAVE-2 and WAVE-3) permit
assembly of multiprotein complexes with proteins that can affect
actin structure such as the Arp2/3 (see below and also Bear et al.,
1998; Machesky and Insall, 1998; Volkmann et al., 2001; Rodal
et al., 2005; Takenawa and Suetsugu, 2007; Pollitt and Insall, 2009).
Rac signaling is also coordinated by the WAVE (Wiskott–Aldrich
syndrome protein family)/Scar (suppressor of cAMP receptor)
family of scaffolding proteins (Machesky and Insall, 1998). Loss of
WAVE-1 affects both lamellipodial dynamics and the pattern of
growth cone motility in a way that retards neurite extension
(Soderling et al., 2007). In addition, loss of WAVE-1 leads to
reduction in spine density. Null WAVE mice were impaired in LTP
and LTD. Mice with WAVE mutation that leads to reduced WRP (a
RacGAP) binding were impaired in hippocampal-dependent Morris
water maze memory retention (Soderling et al., 2007). Impairments
in mutant mice were also detected in novel-object
recognition tests performed to assess hippocampal-independent
nonspatial memory. In another study it was shown that targeted
disruption of the WAVE-1 gene generated mice with reduced
anxiety, sensorimotor retardation, and deficits in Morris water
maze and novel-object recognition, but not passive avoidance,
memory (Soderling et al., 2003).
3.2.2. Arp2/3 in actin branching, structural plasticity and memory
Arp2/3 is activated by neuronal WASP and WAVE1 proteins,
downstream of Rho GTPase family members such as Cdc42 and Rac
(Pollard, 2007; Rotty et al., 2013). It initiates branched filament
polymerization to create actin meshworks (Mullins et al., 1998).
The Arp2/3 may be involved in spine actin remodeling and is
enriched in submembrane region surrounding the spine head (e.g.
Ra´cz and Weinberg, 2008; Wegner et al., 2008; Nakamura et al.,
2011; Lippi et al., 2011). Actin turnover defect in spines was
detected following deletion of ArpC3, an essential Arp2/3 subunit
(Kim et al., 2013). Furthermore, postnatal deletion of ArpC3
induces a progressive loss of spines in vivo. ArpC3 is also involved
in structural plasticity and loss of ArpC3 prevents the maintenance
of activity-induced enlarged spines. Interestingly activity-dependent
spine shrinkage was normal in ArpC3 deleted neurons.
Asymmetric spine structural plasticity in ArpC3 deleted neurons
was shown to be followed by an accumulation of filopodia-like
spines and such spines contained less PSD-95, fewer glutamate
receptors and reduced downstream activation of CaMKII. ArpC3f/
f:CamKlla-Cre mice were assessed using Y-maze (working
memory) and novel object recognition tests (episodic memory).
In the Y-maze test the percentage of alternations was significantly
decreased in the adult ArpC3f/f:CamKlla-Cre mice indicating of
impairment in working memory. In the novel object recognition
test ArpC3f/f:CamKlla-Cre mice were severely impaired in shortterm,
long-term and remote memory capabilities.
3.2.3. Insulin receptor tyrosine kinase substrate of 53 kDa (IRSp53)
and memory
Insulin receptor tyrosine kinase substrate of 53 kDa (IRSp53) is
an abundant protein in the postsynaptic density (PSD) that
contains several domains for protein–protein interactions and
regulates Rac-dependent lamellipodia formation through WAVE2mediated
regulation of Arp2/3 and F-actin polymerization (Miki
et al., 2000; Nakagawa et al., 2003; Cheng et al., 2006; Suetsugu
et al., 2006; Abou-Kheir et al., 2008). IRSp53 and the IRS-58 also
regulates Cdc42-dependent filopodia formation via Mena and Eps8
(Miki et al., 2000; Govind et al., 2001; Krugmann et al., 2001;
Disanza et al., 2006). NMDA receptor activation is needed for
IRSp53 accumulation in spines and specifically in excitatory
synapses (Hori et al., 2005). Furthermore, it was shown that actin
cytoskeleton is involved in the NMDA receptor-mediated synaptic
translocation of IRSp53 as NMDA stimulation did not lead to
synaptic translocation of IRSp53 in neurons pretreated with
latrunculin A. In addition, it was shown that the synaptic
translocation of IRSp53 enhances the postsynaptic activity. The
roles of IRSp53 in neuronal functions and memory were studied in
knockout mice (Kim et al., 2009b). IRSp53 deficiency had no effect
on spine density and ultrastructure, basal synaptic transmission,
presynaptic release and evoked and spontaneous AMPA receptormediated
synaptic transmission. However, IRSp53À/À mice
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exhibited a reduced AMPA/NMDA ratio of excitatory transmission
and enhanced NMDA receptor-mediated transmission and LTP.
IRSp53À/À mice were impaired in Morris water maze and novel
object recognition learning and memory.
3.2.4. Abi family of proteins in memory formation
Additional proteins that interact with WAVE are the Abi1 and
Abi2 (Eden et al., 2002; Soderling et al., 2002). During passive
avoidance training, wild-type, Abi2+/À, and Abi2À/À mice were
equally likely to cross rapidly to the darkened chamber but when
tested at 0.5, 1, or 24 h later, wild-type mice showed substantially
longer latencies to cross to the dark chamber relative to Abi2+/À
and Abi2À/À mice. This observation indicates that Abi2+/À and
Abi2À/À mice are deficient in short- and long-term memory
formation.
Taken together, the above findings show that proteins that bind
to WAVE or WASP (see also profilin below) are involved in memory
formation. It is therefore possible that a complex of proteins
including the scaffolding proteins WAVE and WASP work in a
coordinated manner to convert signals from protein–protein and
membrane-protein interactions to actin polymerization to regulate
actin dynamic in discrete neuronal locations (e.g. activated
synapses) needed for neuronal changes such as spine morphogenesis
that support memory formation.
3.2.5. Filamin, a F-actin cross linker protein, in memory formation
Filamins are large actin-binding proteins that stabilize actin
webs by crosslinking F-actin and linking them to cellular
membranes (Stossel et al., 2001). It was shown that abnormal
expressions levels of cheerio, the Drosophila fly homolog of Filamin
A, are associated with specific defects in LTM memory formation
after Pavlovian olfactory learning (Bolduc et al., 2010).
3.2.6. EPS8, an actin capping protein, is involved in memory formation
Eps8 is involved in actin remodeling through actin barbed end
capping and actin bundling activities (Disanza et al., 2004, 2006). In
Eps8 KO mice a significantly higher number of presynaptic and
postsynaptic puncta were detected in the hippocampus (Menna
et al., 2013). The structural organization of the presynaptic
compartment is not altered in Eps8 KO mice but there is a clear
alteration in the morphology of spines, which appeared thinner
and were significantly longer. The authors also show that actincapping
activity of Eps8 is required for proper mushroom-type
spine formation. In addition, a significant increase in protrusions
per unit length was detected on secondary branches of CA1
neuronal dendrites in the Eps8 KO. In addition, the study unveil
that the capping activity of Eps8 is essential for LTP-mediated
synapse formation and strengthening. Radial maze, novel object
recognition, passive avoidance learning and memory are impaired
in Eps8 knockout mice (Menna et al., 2013). Importantly, structural
plasticity after learning is impaired in mutant mice trained for
object recognition. These mice did not display any increase in spine
number, which shown in wt mice 24 h after training in
hippocampus.
3.2.7. Drebrin A, an actin stabilizing protein, in memory formation
Drebrin is an actin-binding protein enriched in spines (Hayashi
et al., 1996; Aoki et al., 2005; Sekino et al., 2007) and is involved in
stabilizing actin filaments through its effect on their inter-strand
and intra-strand contacts (Mikati et al., 2013). Drebrin has several
isoforms where drebrin E is an embryonic isoform and drebrin A is
an adult isoform (reviewed in Sekino et al., 2007; Kojima et al.,
2010). The isoform conversion is parallel with synapse maturation.
Kojima et al. (2010) generated knockout mice in which a drebrin Aspecific
exon was deleted leading to a mouse (termed DAKO)
expressing drebrin E instead of drebrin A. DAKO mice show no
apparent abnormalities in their gross brain morphology and
general behaviors. DAKO mice are however impaired in long-term
contextual, but not auditory, fear conditioning memory.
3.2.8. Adducin, an actin filament barbed end capping protein, is
needed for memory formation
Adducins cap and bundle actin filaments, and promote spectrin
binding to actin filaments (Gardner and Bennett, 1987; Mische et al.,
1987; Kuhlman et al., 1996). Calmodulin binding and phosphorylation
by protein kinase A (PKA) and protein kinase C (PKC) can
detach adducins from the barbed ends of filamentous actin
(Matsuoka et al., 1996, 1998). The mammalian adducin family is
encoded by three genes (a, b, and g) with various splice variants
(Suriyapperuma et al., 2000). Functional adducin is composed of
heterodimers or heterotetramers of a/bor a/gsubunits(Dong et al.,
1995; Hughes and Bennett, 1995). The roles of adducin in synaptic
plasticity and memory were studied in several adducin mutant mice
lines. Hippocampal CA1 short- and long-term synaptic plasticity is
impaired in b-adducin knock-out mice (Rabenstein et al., 2005).
Spines of the b-adducin knock-out mice appear normal. b-adducin
knock-out animals were impaired in performance of both the Morris
water maze memory and long-term cued and contextual fear
conditioning memory tests compared with their wild-type littermates
(Rabenstein et al., 2005). Mice lacking b-adducin fail to
assemble new synapses upon enhanced plasticity (Bednarek and
Caroni, 2011). Environmental enrichment leads to stable assembly
of new synapses which is dependent on b-adducin, and disassembly
of synapses engages b-adducin phosphorylation via PKC. In the
absence of b-adducin, enrichment still cause an increase in spine
structures, however the assembly of synapses at those spines is
compromised. b-adducin was shown to be needed for environmental-enhanced
long-term memory of contextual fear conditioning
and novel object recognition. b-adducin was not needed for
enrichment-enhancement of short-term memory. In another study
it was shown that in Add2À/À mice average values of filopodia per
large mossy fiber terminal (LMT) were similar to those in wild-type
mice.Add2À/À miceexhibitenhancedputativereleasesitespercore
LMT upon fear conditioning but they were impaired in establishing
higher numbers of filopodia upon fear conditioning. Add2À/À mice
learned contextual fear conditioning but the memory was inexact
and mice starts to generalized 1 day after learning. Similar findings
were observed in Morris water maze and rotarod learning in Add2À/
À mice (Ruediger et al., 2011). Thus, lack of learning-related
feedforward inhibition connectivity growth in mice lacking badducin
is correlated with poor accuracy of fear conditioning and
Morris water maze memories. Another study show that b-adducin
KO mice exhibit behavioral, motor coordination, learning deficits
and are impaired in LTP and LTD (Porro et al., 2010). In the nematode
Caenorhabditis elegans (C. elegans), the loss of a-adducin (add-1)
selectively impaired short- and long-term aversive olfactory
associative memory without causing acquisition, sensory, or motor
deficits (Vukojevic et al., 2012). Moreover, it was found that the
memory and consolidation of synaptic plasticity likely requires the
barbed-end capping activity of ADD-1. Cytochalasin B, a wellcharacterized
compound that inhibits actin polymerization by
binding to the barbed end of actin filaments, rescued the memory
defect of add-1 mutant worms. In humans, genetic variability of the
ADD1 gene is associated with episodic memory performance in
healthy young subjects. Human ADD1 expression in nematodes
restored loss of C. elegans add-1 gene function (Vukojevic et al.,
2012).
3.2.9. Tropomodulin, a pointed-end capping protein, is involved in
memory formation
Tropomodulin binds to actin filament pointed end and prevents
both elongation and depolymerization (Yamashiro et al., 2012). To
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study the roles of Tropomodulin in behavior Cox et al. (2003)
generated a Tropomodulin2 knockout mice (Tmod2lacZÀ/À).
Tmod2lacZÀ/À mice exhibited no gross morphological or anatomical
abnormalities, but were found to be hyperactive and with
reduced sensorimotor gating. Tmod2lacZÀ/À mice had enhanced
LTP but no impairments in synaptic transmission or paired-pulse
facilitation (PPF). Tropomodulin KO mice were impaired in
contextual and cued conditioned fear and Morris water maze
memory formation.
3.2.10. Spinophilin and Neubrin are actin binding proteins involved in
memory formation
Neurabin (neurabin I) and spinophilin (neurabin II) are
structurally similar cytoskeletal binding proteins that bind F-actin
in the brain (Allen et al., 1997; Nakanishi et al., 1997; Satoh et al.,
1998) and are implicated in regulation of neuronal morphology
(e.g. Sarrouilhe et al., 2006). Neurabin KO mice showed a
significant reduction in contextual fear memory 1 h, 1 day and 3
days after conditioning (Wu et al., 2008). Auditory fear memory
was unaltered in neurabin KO mice. LTP in hippocampal CA1
neurons was significantly reduced whereas LTD was unaffected.
Increased AMPA receptor but not NMDA receptor-mediated
synaptic transmission was detected in neurabin KO mice.
Spinophilin knockout mice were unable to learn a conditioned
taste aversion (CTA) when sucrose or NaCl solutions were paired
with a moderate dose of LiCl (Stafstrom-Davis et al., 2001).
3.2.11. Profilin, an actin monomer binding protein, in memory
formation
Profilin is another actin cytoskeleton-regulatory protein
involved in actin polymerization by funneling ATP-actin to the
growing actin filaments (Witke, 2004). Profilin was shown to be
translocated into spines in hippocampal neurons after neuronal
stimulation, LTP or LTD (Ackermann and Matus, 2003; Neuhoff
et al., 2005). Profilin movementis associated with the suppression
of actin dynamics in the spine head and the stabilization of spine
morphology. Fear conditioning in rats induces the translocation of
profilin into spines in LA (Lamprecht et al., 2006a). Profilincontaining
spines were shown to be larger compared to spines
devoid of profilin. Increase in profilin-containing spines with
enlarged PSDs could contribute to the enhancement of associatively
induced synaptic responses in LA following fear learning. Mice
with knockdown of one of the profilin isoforms, profilin2, are
hyperactive and exhibit increased novelty-seeking behavior (Pilo
Boyl et al., 2007). Freezing after fear conditioning is similar in
control and knockout mice when number of freezings, but not time
of freezing, is monitored during LTM test (Pilo Boyl et al., 2007).
Taken together the above observations indicate that the actin
cytoskeleton is tightly regulated by multiple actin regulatory
proteins and that interference with this regulation affects synaptic
plasticity, structural plasticity and memory formation. The proteins
described above controls actin dynamic, stability and structure to
produce an appropriate cytoskeleton structure mediating morphology
and transmission (see below). Actin can mediate other cellular
functions such as contractility and cellular transport by serving as a
platform for the motor protein myosin as described below.
3.3. The actin binding motor protein myosin in memory formation
Myosins are motor proteins that interact with actin filaments
and hydrolyze ATP to produce movement and force (Kneussel and
Wagner, 2013). This process allows myosins to drive the sliding of
actin filaments, to produce tension on actin filaments and to
advance along these filaments. As a consequence, myosins can
regulate the structure and dynamics of the actin cytoskeleton and
affect the localization and transport of cellular components.
It was shown that myosin and it regulatory proteins are
involved in brain actin dynamics, synaptic plasticity and memory
formation. Rex et al. (2010) showed that myosin IIb expression is
involved in actin dynamics following the induction of LTP and is
important for stabilization, but not induction, of early LTP. These
investigators further demonstrated that injection of AAV to
express MyH10 shRNAs or the specific inhibitor of myosin II
ATPase activity, Blebbistatin (Blebb) (Kovacs et al., 2004; Limouze
et al., 2004; Allingham et al., 2005) into the CA1 impaired longterm
contextual fear conditioning memory. They also show that
myosin II drives cytoskeletal changes needed for LTM formation
that occur during, or very shortly after, the hippocampusdependent
associative training.
Infusion of blebb, directly into rats LA 30 min prior to cued fear
conditioning impaired long-term, but not short-term, fear memory
formation (Gavin et al., 2011). Intra-LA injections of recombinant
adeno-associated virus (rAAV) particles expressing short hairpin
RNA (shRNA) targeting Myosin IIB also impaired fear LTM.
Myosin light chain kinase (MLCK) is a calcium/calmodulindependent
protein kinase that phosphorylates the myosin regulatory
light chain (RLC), leading to contraction of the actomyosin
filaments (Kamm and Stull, 2001; Somlyo and Somlyo, 2003). MLCK
is involved in regulating cellular processes related to synaptic
transmission, such as neurotransmitter release (Mochida et al.,
1994; Ryan, 1999; Polo-Parada et al., 2001), NMDA receptor function
(Lei et al., 2001) and potassium channel current modulation (Akasu
et al., 1993). In addition, MLCK is involved in neural morphogenesis,
including the regulation of growth cone motility (Gallo et al., 2002;
Zhou et al., 2002) and dendritic branching (Ramakers et al., 2001).
MLCK was shown to be involved in fear memory formation in LA.
MLCK is present in cells throughout the LA and is localized to
dendritic shafts and spines that are postsynaptic to the projections
from the auditory thalamus to lateral nucleus of the amygdala, a
pathway implicated in fear learning (Lamprecht et al., 2006b).
Inhibition of MLCK in LA by microinjection of ML-7 (1-(5iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine
hydrochloride),
an inhibitor of MLCK, led to the enhancement of fear
memory formation but had no effect on retrieval of fear memory
(Lamprecht et al., 2006b). MLCK inhibition immediately following
fear conditioning training had no effect on fear memory. The brevity
time window of involvement of MLCK in fear conditioning is
consonant with its ability to rapidly regulate synaptic transmission
(Ryan, 1999; Lei et al., 2001). In addition, findings showing that
MLCK is located in LA presynaptic terminals and in postsynaptic
densities suggest that MLCK might be involved in regulating
processes in these sites such as vesicle release (Ryan, 1999) or
receptor activity (Lei et al., 2001). Moreover, the observation that
MLCK inhibition does not affect fear memory retrieval implies that
MLCK does not regulate transmission during memory activation, but
only during acquisition. In addition, inhibition of myosin light chain
kinase increased LTP in the auditory thalamic pathway to the LA
(Lamprechtetal.,2006b).ApplicationofML-7toamygdalasliceshad
no effect on basal transmission but rather specifically on the
induction of associative LTP. These findings show that the inhibition
of MLCK facilitates conditioning and synaptic plasticity and indicate
that MLCK normally inhibits fear learning.
3.4. MicroRNAs control of actin regulatory proteins in memory
MicroRNAs (miRNAs) are endogenous noncoding RNAs that are
able to mediate cleavage or translational repression of their target
mRNAs by direct binding to the 30
-UTR of target mRNAs (Filipowicz
et al., 2008; Bartel, 2009). MiRNA targets include actin regulatory
proteins. For example, the brain-specific microRNA, miR-134, is
localized to the synapto-dendritic compartment of rat hippocampal
neurons and negatively affects the size of spines by inhibition
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of the translation of an mRNA encoding LIMK-1 (Schratt et al.,
2006). Exposure of neurons to extracellular stimuli relieves miR-
134 inhibition of LIMK-1 translation. Thus, the expression of
miRNA can affect its target translation. Griggs et al. (2013)
performed a microarray analysis in lateral amygdala 1 hr after fear
conditioning. They revealed that miRNAs that can potentially
repress the translation of actin-regulating proteins are downregulated
after training. Overexpression of one of these downregulated
miRNAs, miR-182, within the lateral amygdala resulted
in decreased levels of the actin regulatory proteins cortactin and
Rac1. The overexpression of miR-182 also impaired long-term but
not short-term auditory fear memory. Thus, actin regulatory
proteins are also being controlled at the protein level following
learning. The effects of such changes may be related to later
neuronal alterations needed for memory formation not immediately
after learning.
Cumulatively, the aforementioned studies show that actin
regulatory proteins are intimately involved in memory formation.
Modulation of the actin cytoskeleton by these proteins may serve
as a cellular signaling that connects synaptic activation initiated by
learning to the cellular changes underlying memory formation. To
further elucidate possible roles of actin cytoskeleton in memory
formation the participation of actin cytoskeleton in synaptic
morphology, transmission and plasticity in neurons is discussed
below.
4. Actin cytoskeleton in synaptic transmission
Alteration of synaptic strength by affecting synaptic release of
neurotransmitters and/or the level of synaptic receptors for
neurotransmitters is associated with memory formation and
synaptic plasticity. Changes in synaptic efficacy are induced by
learning. For example, it was shown that fear-conditioning lead to
presynaptic facilitation of AMPA receptor-mediated transmission
in LA neurons (McKernan and Shinnick-Gallagher, 1997) and
conditioned fear is accompanied by an enhancement of transmitter
release at cortico-amygdala synapses (Tsvetkov et al., 2002). At the
postsynapse fear conditioning drives AMPA receptors into LA
synapses, a process that is needed for fear conditioning memory
formation (Rumpel et al., 2005; Yeh et al., 2006; Nedelescu et al.,
2010). Inhibitory avoidance (IA) drives AMPA receptors subunits
into hippocampal synapse (Whitlock et al., 2006) and IA produces
an enhancement of field excitatory postsynaptic potential (fEPSP)
in hippocampus (Whitlock et al., 2006). Fear conditioning leads to
recruitment of newly synthesized GluR1 selectively to mushroomtype
spines in adult hippocampal CA1 neurons (Matsuo et al.,
2008). Olfactory discrimination learning induces enhancement in
the averaged amplitude of AMPA receptor-mediated miniature
synaptic events in piriform cortex pyramidal neurons (Saar et al.,
2012). GABA receptors are also involved in learning and memory
for example, the averaged amplitude of GABA(A) receptormediated
miniature inhibitory synaptic events was significantly
enhanced following odor discrimination training (Saar et al., 2012).
Actin cytoskeleton located in pre- and post-synapse is involved
in the regulation of synaptic transmission in these sites and may
mediate changes in synaptic efficacy following learning. In the
presynapse actin cytoskeleton contacts synaptic vesicle through
short strands of synapsin, a phosphoprotein associated with
synaptic vesicle membrane (e.g., Landis et al., 1988; Hirokawa
et al., 1989; Doussau and Augustine, 2000). It is possible that actin
regulates the availability of the vesicles in the reserve pool (RP) by
forming a barrier (e.g., Wang et al., 1996) or may serve as a scaffold
protein to retain synapsin in presynapse, thereby indirectly
affecting neurotransmission (Sankaranarayanan et al., 2003).
Neuronal activation may redistribute synapsin allowing access
to the RP of vesicles (Greengard et al., 1994; Chi et al., 2001, 2003).
Actin may also promote vesicle delivery to the readily releasable
pool (RRP) by providing cytoskeletal routes of vesicle to the RRP
(Prekeris and Terrian, 1997; Evans et al., 1998; Watanabe et al.,
2005). In addition, actin may be involved in the endocytosis of
vesicle at the presynapse, possibly by forming a link with dynamin
or by promoting the transport of endocytosed vesicles to the
internal RP cluster (Shupliakov et al., 2002; Bloom et al., 2003;
Engqvist-Goldstein and Drubin, 2003). Synaptic vesicles endocytosed
at one bouton can be recruited into the functional pool of
nearby boutons where they undergo exocytosis (Darcy et al., 2006).
Such distribution of vesicles between nearby boutons requires
actin turnover (Darcy et al., 2006).
The postsynaptic actin cytoskeleton may affect synaptic
transmission as it is involved in the regulation of glutamate and
GABA receptors clustering and trafficking and by that means the
postsynaptic response to neurotransmitters. F-actin depolymerization
leads to a decrease in the number of AMPA and NMDA
receptors clusters at excitatory synapses (Allison et al., 1998). Actin
may also mediate glutamate receptors trafficking via myosins.
Myosin Va mediates translocation of GluR1-containing AMPA
receptor (AMPAR) from the dendritic shaft into spines and is
needed for LTP (Correia et al., 2008). Myosin Vb is also involved in
AMPAR trafficking (Lise´ et al., 2006; Wang et al., 2008). Actin
regulatory and associated proteins are also involved in receptor
trafficking. For example, ADF/cofilin-mediated actin dynamics
regulates AMPAR translocation during synaptic potentiation (Gu
et al., 2010). The reversion induced LIM protein (RIL) is involved in
actin-dependent trafficking of the AMPAR subunit GluR1 (Schulz
et al., 2004) and the actin adaptor protein 4.1 N regulates the
surface expression of GluR1 (Shen et al., 2000, Hayashi et al., 2005;
Lin et al., 2009). The actin cytoskeleton also mediates AMPAR
internalization. AMPAR internalization can be induced by the actin
assembly inhibitor latrunculin A, and is blocked by jasplakinolide,
a drug which stabilizes actin filaments (Zhou et al., 2001). Myosin
VI plays a role in the clathrin-mediated endocytosis of AMPARs
(Osterweil et al., 2005). Actin cytoskeleton can also affect
inhibitory transmission by mediating GABA receptor trafficking
to the synapse (e.g., Graziane et al., 2009).
Cumulatively, the aforementioned studies show that actin
cytoskeleton is involved in regulating synaptic transmission by
affecting pre- and post-synapse molecular and cellular events that
are also involved in synaptic plasticity and memory formation.
Additional research is warranted to determine whether actin
cytoskeleton is needed for presynaptic or postsynaptic alterations
during and following learning.
5. Actin cytoskeleton in synaptic morphogenesis
It has been shown that alteration in neuronal morphology is
associated with memory formation (Bailey and Kandel, 1993;
Lamprecht and LeDoux, 2004) and may be needed to modulate
neuronal connectivity to form or alter memory. Most excitatory
synapses in the brain terminate on spines, which have been the
focus of recent studies pertaining to the mammalian brain. Spines
receive the majority of excitatory synaptic inputs in the brain,
compartmentalize local synaptic signaling pathways, and confine
the diffusion of postsynaptic molecules (Nimchinsky et al., 2002;
Lamprecht and LeDoux, 2004; Newpher and Ehlers, 2009).
Modulation of the number of spines and/or their morphology
has been proposed to contribute to changes in excitatory synaptic
transmission following learning (Lamprecht and LeDoux, 2004).
Changes in number and shape of spines were observed following
learning. For example, an increase in spine number (density) was
detected in the hippocampus 24 h after trace eyeblink conditioning,
and these changes were blocked by NMDA antagonists
(Leuner et al., 2003). An increase in the number of multiple
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synaptic boutons that formed synapses on spines was also
detected in the hippocampus 24 h after trace eyeblink conditioning
(Geinisman et al., 2001). The number of synapses also increases in
the cerebellum after eyeblink conditioning (Kleim et al., 2002) and
in the piriform cortex following olfactory learning (Knafo et al.,
2001). Repetitive motor learning leads to coordinated formation of
clustered spines (Fu et al., 2012). In zebra finches, hearing a tutor
song led to the rapid stabilization, accumulation and enlargement
of spines in HVC (Roberts et al., 2010). In addition, contextual fear
conditioning leads to a time-dependent increase in spine density in
the CA1 hippocampal area and in the anterior cingulate cortex
(Restivo et al., 2009; Vetere et al., 2011) and auditory fear
conditioning leads to an increase in spinophilin-immunoreactive
spines in the LA (Radley et al., 2006). Postsynaptic density (PSD)
area on a smooth endoplasmic reticulum (sER)-free spines
increases with fear conditioning whereas the spines head volume
of these spines decreases (Ostroff et al., 2010).
Actin cytoskeleton is involved in neuronal morphogenesis in
postsynaptic spines. The base, neck, and head of mature spine
contain a mixture of branched and linear actin filaments. The neck
includes both linear and branched filaments, whereas branched
actin filament network is a dominant feature of spine head
(Korobova and Svitkina, 2010). The actin cytoskeleton is intimately
involved in the formation, elimination, stability, motility and
morphology of spines (e.g., Halpain et al., 1998; Matus, 2000;
Korkotian and Segal, 2001; Luo, 2002; Ethell and Pasquale, 2005;
Tada and Sheng, 2006; Schubert and Dotti, 2007; Honkura et al.,
2008; Hotulainen and Hoogenraad, 2010). In addition, actin plays a
role in stabilizing postsynaptic proteins (Allison et al., 1998; Kuriu
et al., 2006; Renner et al., 2009) and in modulating spine head
structure following synaptic signaling (Fischer et al., 2000; Star et al.,
2002; Okamoto et al., 2004). Ample studies have shown that actin
regulatory proteins are also involved in regulating spine morphology
(see above). For example, proteins that are involved in actin
polymerization and depolymerization such as profilin (e.g. Ackermann
and Matus, 2003) and cofillin (e.g. Rust et al., 2010) or
proteins involved in actin branching such as Arp2/3 (e.g. Ra´cz and
Weinberg, 2008; Wegner et al., 2008; Nakamura et al., 2011; Lippi
et al., 2011) have been shown to regulate spine morphogenesis. Such
proteins can couple intra- or extra-cellular signaling to neuronal
morphogenesis by controlling actin dynamics and structure.
Alteration in axonal morphology is also implicated in synaptic
plasticity and memory formation (Bailey and Kandel, 1993;
Lamprecht and LeDoux, 2004). Actin polymerization mediates
morphological changes involved in axonal growth, guidance,
shape, collateral branching, branch retraction and regeneration
(Luo, 2002; Letourneau, 2009).
Additional research is warranted to elucidate whether actin is
involved in neuronal morphogenes is observed after learning and
whether such changes are essential for memory formation. Some
supporting evidence comes from studies showing that interference
with actin regulatory proteins activity impairs memory formation
and spine and axonal morphology (e.g. LIMK-1 (Meng et al., 2002);
cofillin (e.g. Rust et al., 2010); ArpC3 (Kim et al., 2013); and see
above).
6. The roles of actin cytoskeleton in synaptic plasticity
6.1. Synaptic plasticity and memory
As shown in the aforementioned studies actin cytoskeleton plays
central roles in modulating synaptic transmission and neuronal
morphogenesis, cellular processes believed to subserve synaptic
plasticity (e.g. Bailey and Kandel, 1993; Lamprecht and LeDoux,
2004). The role of actin cytoskeleton in synaptic plasticity was
studied mainly by elucidating its involvement in LTP or LTD,
physiological models of memory (e.g., Bliss and Collingridge, 1993;
Malenka and Nicoll, 1999; Martin et al., 2000). Findings relate LTP
and LTD with learning and memory (e.g. Lynch, 2004, Collingridge
et al., 2010). For example, inhibitors and genetic manipulation that
impair hippocampal LTP also block hippocampal learning and
memory retention. Intraventricular injection of the NMDA receptor
antagonist AP-5 impaired hippocampal LTP and Morris water maze
memory formation (Morris et al., 1986) and mice in which the
deletion of the NMDAR1genewas restricted tothe hippocampalCA1
pyramidal cells were impaired in LTP in the CA1 synapses and in
spatial memory (Tsien et al., 1996). One-trial inhibitory avoidance
(IA) learning in rats produced similar changes in hippocampal AMPA
glutamate receptors as induction of LTP with high frequency
stimulation and caused a spatially restricted increase in the
amplitude of evoked synaptic transmission in CA1 in vivo. On the
basis of the observation that learning-induced synaptic potentiation
occluded HFS-induced LTP, the authors conclude that IA training
induces LTP in CA1 (Whitlock et al., 2006). Studies suggest that LTP
occurs in the LA and hippocampus during fear conditioning. LTP
induction at thalamic auditory inputs to the LA facilitates auditoryinduced
responses in the LA similarly to the increase of CS-evoked
responses observed during auditory fear conditioning (Rogan and
LeDoux, 1995). In addition, fear conditioning-altered auditory CSevoked
responses in LA changes together with conditioned fear
responses (Rogan et al., 1997). Thalamic inputs or cortical inputs to
the LA were enhanced in brain slices from trained animals compared
to naive or unpaired animal groups (McKernan and ShinnickGallagher,
1997). Moreover, fear conditioning inhibits the induction
of LTP at cortical inputs suggesting that LA synapses that have
already undergone LTP by training are less capable of inducing LTP
(Tsvetkov et al., 2002; Schroeder and Shinnick-Gallagher, 2004; and
Schroeder and Shinnick-Gallagher, 2005). Studies have shown that
contextual fear conditioning increased synaptic responses in
hippocampal CA1 (e.g., Sacchetti et al., 2001) and that contextual
fear conditioning altered the ability to induce LTP in hippocampus
(Sacchetti et al., 2002). LTD is also implicated in learning and
memory (e.g. Collingridge et al., 2010). For example, blocking the
interactions between GluR2 and AP2 impaired LTD in perirhinal
cortex in vitro and produced striking deficits in visual object
recognition memory (Griffiths et al., 2008).
6.2. Actin in LTP
To study the roles of actin in LTP Okamoto et al. (2004) utilized
the fluorescence resonance energy transfer (FRET) technique to
show that LTP in rat hippocampal spines led to persistent shift of Factin/G-actin
equilibrium toward F-actin within seconds of a
tetanic stimulus. In the dentate gyrus, LTP increased F-actin
content in spines lasting up to 5 weeks (Fukazawa et al., 2003). The
increase in F-actin correlated with increase in the size of the spine
head and inhibition of actin polymerization impaired LTP-induced
spine head enlargement (Matsuzaki et al., 2004; Okamoto et al.,
2004; Fortin et al., 2010). LTP also induced alterations in axonal
morphology and actin cytoskeleton leading to creation of new
axonal varicosities and new axonal actin puncta (Colicos et al.,
2001; De Paola et al., 2003). The new presynaptic actin puncta
become associated with recycling synaptic vesicle pool (Colicos
et al., 2001). Long-term facilitation leads to the growth of new
synapses and presynaptic actin remodeling in Aplysia mechanosensory
neurons (Hatada et al., 2000). In addition, cytochalasin D
selectively impairs long-term but not short-term facilitation (Udo
et al., 2005).
In LA, 5-HT-induced L-LTP is blocked by the actin inhibitor
cytochalasin D (Huang and Kandel, 2007). Furthermore, LTP in
interneurons in LA is maintained by trafficking of GluR2-lacking
AMPA receptors that need an interaction with SAP97 and the actin
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cytoskeleton (Polepalli et al., 2010). Inhibition of actin polymerization
in hippocampus or disruption of F-actin cause an
impairment of LTP formation and facilitation (e.g., Kim and
Lisman, 1999; Krucker et al., 2000; Fukazawa et al., 2003; Krama´r
et al., 2009). In addition, inhibition of actin polymerization affects
protein synthesis-independent early LTP, prevents late-LTP, and
interferes with synaptic tagging in apical dendrites of hippocampal
CA1 (Ramachandran and Frey, 2009). Furthermore, chemical forms
of LTP in hippocampal cultures forms GluR1 and synaptophysin
puncta and these cellular and molecular events require actin
polymerization (Antonova et al., 2001). Taken together, the above
observations indicate that the actin cytoskeleton is needed for LTP.
6.3. Actin in LTD
Actin cytoskeleton is also involved in LTD which in many
instances induces opposite synaptic, morphological, and molecular
events compared to LTP (e.g., Zhou et al., 2004; Asrar and Jia, 2013).
LTD induces shifts the F-actin/G-actin equilibrium toward G-actin
and decreases spine head volume with the disappearance of some
spines (Okamoto et al., 2004). The actin stabilizing drug jasplakinolide,
a compound that has also been reported to block AMPA
receptor endocytosis (Zhou et al., 2001), was shown to prevent the
long-lasting depressioninduced by(S)-3,5-Dihydroxyphenylglycine
(DHPG), a specific group I metabotropic glutamate receptor (mGluR)
agonist, in hippocampus neurons (Xiao et al., 2001). In another study
the investigators infused the actin stabilizer phalloidin into
hippocampal cells and observed that LTD was blocked (Morishita
et al., 2005). Cofilin is also shown to be involved in regulating LTD
(Zhou et al., 2004; Morishita et al., 2005). GluA2 regulates
metabotropic glutamate receptor-dependent long-term depression
(mGluR-LTD) in N-cadherin-dependent and cofilin-mediated actin
reorganization (Zhou et al., 2011). Furthermore, LTD-inducing
paradigm has stabilizing effects on actin (Star et al., 2002).
6.4. Actin regulatory proteins in synaptic plasticity
6.4.1. Rho GTPases and synaptic plasticity
Synaptic plasticity is regulated by Rho GTPase family of proteins
shown to be involved in memory formation. For example, in
hippocampus the activation of RhoA and Rac1 by high frequency
stimulation was attenuated by geranylgeranyl transferase inhibitor
GGTI-287 and activation of RhoB was largely prevented by FTase
inhibitor 1 (FTase inhibitor 1 can also reduce the levels of activated
Ras). FTase inhibitor 1 reduced the magnitude of LTP while GGTI-
287 markedly enhanced the magnitude of LTP. Inhibition of ROCK
also increased the magnitude of LTP (O’Kane et al., 2004). In another
study it was shown that early phase LTP is significantly reduced in
RhoBÀ/À animals, whereas the later phase is unaffected (McNair
et al., 2010). RhoB is also involved in the regulation of cofilin and
dendritic and spine morphology (McNair et al., 2010). A general
inhibitor of Rho GTPases, Clostridium difficile toxin B, significantly
reduced the glutamate-induced potentiation of mEPSC frequency in
hippocampal neurons (Wang et al., 2005). Inhibition of ROCK also
reduced the potentiation of mEPSC frequency and amplitude.
Inhibition of Rac1 GTPase in the hippocampus impaired the
induction of NMDA receptor-dependent LTP, but did not have an
effect on LTP maintenance and expression. The Rac1 GTPase
inhibitor also impaired NMDA receptor-dependent induction of
LTD, while mGluR-dependent LTD was shown to be altered but not
eliminated (Martinez and Tejada-Simon, 2011). Adenosine infusion
blocked theta burst stimulation (TBS)-induced actin polymerization
within spines along with LTP itself in hippocampal slices but not in
those slices pretreated with jasplakinolide that stabilizes actin
filament (Rex et al., 2009). The authors further showed that the
ROCK inhibitor reduced TBS-induced cofilin phosphorylation, spine
actin polymerization and LTP. Inhibitors of Rac or PAK did prolong
LTP’s vulnerability to reversal by latrunculin. Ptprz-deficient mice
that are impaired in memory formation (see above) exhibit
enhancement of LTP in the CA1 region in hippocampal slices that
is obliterated by pharmacological inhibition of ROCK (Niisato et al.,
2005). Loss of Rac1 impaired LTP in both CA1 and dentate gyrus
(Haditsch et al., 2009).
Cumulatively, the above observations suggest that stimuli that
lead to induction of LTP activate synaptic receptors and modulate
intracellular signaling proteins that regulate actin dynamics and
structure. Interfering which such regulation impairs actin cytoskeleton
responses to receptors activation and leads to impairments
in synaptic plasticity.
6.4.2. Actin binding proteins and synaptic plasticity
Neuronal plasticity is also modulated by actin binding proteins.
For example, the actin-capping protein, Eps8, is recruited to the
spine head during LTP and inhibition of Eps8 capping activity
impairs spine enlargement and potentiation (Menna et al., 2013).
Another study shows that Eps8 induces the formation and
maturation of spines and regulates actin dynamics and the balance
between excitatory synapses on spines and the dendritic shaft
(Stamatakou et al., 2013). This study also shows that Eps8 is
needed for LTP-dependent structural plasticity of spines. Adducin,
involved in actin capping, bundling, and in promoting spectrin
binding to actin filaments (Gardner and Bennett, 1987; Mische
et al., 1987; Kuhlman et al., 1996), is also needed for synaptic
plasticity. b-adducin is needed for CA1 short- and long-term
synaptic plasticity (Rabenstein et al., 2005). Mice lacking Tmod2,
that encodes the actin capping protein Tropomodulin-2, have
normal basal synaptic transmission at Schaffer collateral synapses
as shown by input/output curves and the amplitude of the fiber
volley (Cox et al., 2003). Paired-pulse facilitation (PPF) which
indicates on presynaptic neurotransmitter release is normal in
Tmod2 null mice. The study shows that there is an enhancement in
LTP following PTP in mice lacking Tmod2 that could reflect an
enhancement in induction or maintenance of LTP and suggesting
that Tmod2 plays a role in synaptic plasticity.
Cumulatively, the aforementioned studies show that the actin
cytoskeleton serves as regulator of synaptic plasticity possibly by
affecting synaptic morphology and transmission and thereby
tuning synaptic efficacy. Furthermore, the actin cytoskeleton is
intimately involved in synaptic plasticity in brain regions involved
in memory formation such as the amygdala and hippocampus.
7. Conclusions and discussion
Several additional conclusions and insights can be drawn from
the above observations: (1) Although actin is involved in basic
fundamental functions such as synaptic transmission and neuronal
morphogenesis many studies show that interfering with actin
cytoskeleton, or its regulatory proteins, functions has no effect on
basal synaptic transmission but specifically on synaptic plasticity
and memory formation. A tenable hypothesis is that actin
cytoskeleton affects synaptic properties needed specifically for
alterations in synaptic efficacy in a stimuli-dependent manner.
These stimuli may be related to learning or stimuli leading to
synaptic plasticity. (2) Table 1 shows that actin-regulatory proteins
subserve the formation of different types of memory (e.g. spatial
memory such as Morris water maze and aversive memory such as
fear conditioning) in different organisms along the phyla. These
observations suggest that different types of memory are mediated
by similar cellular events subserved by the actin cytoskeleton. This
is not unique to actin regulatory pathways as other pathways are
found to subserve various behaviors and memories in different
organisms (e.g. CREB-mediated transcription; Lamprecht, 1999).
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10.1016/j.pneurobio.2014.02.001
Table 1
The roles of actin regulatory proteins in learning and memory.
Proteins Effects on actin and cellular functions Involvement in learning and memory References
Rho GTPase family GAPs and GEFs Affect actin dynamics by regulating Rho
GTPases
p190 RhoGAP Affects actin reorganization; regulates
axonal morphology.
Fear conditioning, Morris water maze. Brouns et al., 2000; Billuart et al., 2001;
Lamprecht et al., 2002; Niisato et al., 2005;
Tamura et al., 2006
Oligophrenin1 Inhibits RhoA, Rac1, and Cdc42;
colocalizes with actin; affects dendritic
spine morphology.
Morris water maze. Fauchereau et al., 2003; Govek et al., 2004;
Khelfaoui et al., 2007.
Breakpoint cluster region (BCR)
and active BCR-related (ABR)
RacGAP, affects dendritic spine density. Morris water maze, object recognition
memory.
Oh et al., 2010.
WRP RacGAP, affects dendritic spine density. Object recognition, water maze, passive
avoidance memory.
Endris et al., 2002; Carlson et al., 2011.
KALRN RacGEF, affects actin dynamics,
glutamatergic transmission, spine density.
Morris water maze, Y-maze paradigm
(KALRN), passive avoidance (kalirin7), fear
conditioning.
Penzes et al., 2000, 2001; Ma et al., 2008
(Kalirin7); Cahill et al., 2009; Xie et al.,
2011; Vanleeuwen and Penzes, 2012.
Rho GTPase family Affects actin dynamics via downstream
signaling proteins
Rac GTPase Affects actin dynamics by regulating
molecules such as PAK, spine and synapse
morphology.
Inhibition/knockout – slower decay of
olfactory aversive conditioning memory
(Drosophila), Impairs cocaine-induced
place preference (CPP), Morris water maze,
contextual fear extinction. Activation –
enhancement of fear conditioning
memory, Morris water maze, object
recognition memory.
Diana et al., 2007; Sananbenesi et al.,
2007; Corbetta et al., 2008; Haditsch et al.,
2009; Shuai et al., 2010, 2011; De Viti et al.,
2010; Borrelli et al., 2013; Ding et al., 2013
Rho GTPase family-regulated
proteins
Affecting actin by controlling
actin-regulatory proteins
Rho-associated kinase Affecting actin functions by regulating
proteins such as myosin light chain
phosphatase and LIM kinase (LIMK).
Fear conditioning, conditioned taste
aversion, Morris water maze.
Lamprecht et al., 2002; Dash et al., 2004;
Ota et al., 2010; Rozic et al., 2011; Sweetat
et al., 2012
p21 activated kinase (PAK) Inhibits cofilin activity via LIMK; affects
dendritic spine number and morphology.
Morris water maze, contextual fear
conditioning, active and passive
avoidance, contextual fear conditioning
memory extinction.
Hayashi et al., 2004; Sananbenesi et al.,
2007; Nekrasova et al., 2008; Furnari et al.,
2013
LIM-kinase (LIMK) LIMK phosphorylates and inactivates the
actin depolymerization factor cofilin;
affects spine and axonal morphology.
LIMK-1 knockout mice show enhanced
cued fear and impair reversal phase of
Morris water maze.
Meng et al., 2002
Actin binding and regulatory
proteins
Proteins that directly control actin
dynamics and structure
Cofilin Severs and depolymerizes actin filaments;
affects spine number and morphology.
Morris water maze learning, contextual
and cued fear learning, conditioned place
preference reward learning, object
placement training, inhibitory avoidance,
extinction of conditioned taste aversive.
Rust et al., 2010; Suzuki et al., 2011;
Nelson et al., 2012; Wang et al., 2013
Arp2/3 Initiates branched filament
polymerization to create actin
meshworks; affects spine morphology.
Y maze, novel object recognition memory. Kim et al., 2013
Filamin F-actin cross linker protein. Pavlovian olfactory LTM. Bolduc et al., 2010
Eps8 Actin barbed end capping and actin
bundling activities; affects neuronal
morphology.
Radial maze, novel object recognition,
passive avoidance.
Menna et al., 2013
Drebrin A Stabilizing actin filaments. Contextual fear conditioning memory. Kojima et al., 2010
Adducin Caps and bundles barbed end of actin
filaments and promotes spectrin binding
to actin filaments; affects spine
morphology.
Morris water maze, cued and contextual
fear conditioning memory,
environmental-enhanced long-term
memory of contextual fear conditioning
and novel object recognition, olfactory
associative memory.
Rabenstein et al., 2005; Porro et al., 2010;
Bednarek and Caroni, 2011; Ruediger et al.,
2011; Vukojevic et al., 2012
Tropomodulin Pointed-end actin capping protein. Contextual and cued conditioned fear,
Morris water maze.
Cox et al., 2003
Neubrin/spinophilin Actin binding protein. Contextual fear memory, conditioned
taste aversion (CTA).
Stafstrom-Davis et al., 2001; Wu et al.,
2008
Profilin Funnels ATP-actin monomers to the
growing actin filaments; affects spine
morphology.
Fear conditioning in rats induces the
translocation of profilin into dendritic
spine in the LA.
Lamprecht et al., 2006a
Myosin II and myosin light
chain kinase (MLCK)
Actin binding motor protein and regulator. Cued and contextual fear conditioning. Lamprecht et al., 2006b; Rex et al., 2010;
Gavin et al., 2011
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10.1016/j.pneurobio.2014.02.001
(3) The actin cytoskeleton and its regulatory proteins are involved
in various stages of memory. They are involved in memory
consolidation, reconsolidation and extinction. These findings
suggest that similar cellular events mediated by the actin
cytoskeleton are involved in these memory stages. For example,
memory consolidation and extinction involve spine morphogenesis.
(4) Interruption of actin cytoskeleton mediated functions is
sufficient for disruption of memory formation. Other cellular
functions shown to be essential for memory formation such as
protein synthesis could be mediated by actin cytoskeleton or are
needed for memory formation in addition to actin cytoskeleton (at
same or different time points). (5) Studies have shown that proteins
involved in processes leading to opposite outcomes at the molecular
level (e.g. inhibiting or activating Rho GTPase or Rac GTPase) lead to
similarbehavioraloutcomesuchasmemoryimpairment.Itmightbe
that the various pathways affecting actin are activated in different
temporal and spatial manner and the participating proteins are
engaged at different time points during memory formation and at
different micro-regions of the neurons. The studies described in the
review showing the effects of these proteins on memory formation
utilize techniques that affect actin and its regulatory protein in a
relatively low temporal and spatial resolution. Thus, current
techniquesdescribedinstudies do not allow dissectingthe functions
of these proteins at high resolution in vivo.
8. Actin cytoskeleton – a mediator between synaptic signaling
during learning and cellular events involved in memory
formation and extinction
Based on the studies above the following sequence of events
leading to memory formation that involve the actin cytoskeleton is
suggested (Fig.. 2). Learning induces a significant activation of
synaptic receptors and channels above a certain threshold (for fear
conditioning see Blair et al., 2001) leading to the activation of
intracellular signaling pathways and to alteration of actin
cytoskeleton dynamics, actin filaments structure and interaction.
These changes in actin filament may support multiple key cellular
events that include modulation of neurotransmitter receptors at
the synapse and alteration in synapse and spine morphology. Such
changes have shown to alter synaptic efficacy and believed to be
essential for alteration in connectivity between neurons which
constitute the changes in neuronal circuits leading to memory
storage.
9. Future research
Much evidence indicates that the actin cytoskeleton and its
regulatory proteins are involved in memory formation. However,
key questions remain unanswered. For example, are the morphological
changes shown to be mediated by actin cytoskeleton, such
as shown in spines and axons, needed for memory formation? Does
actin cytoskeleton regulate changes in synaptic transmission
needed for memory formation? If so, are they related to
presynaptic (changes in vesicle release) or postsynaptic (changes
in receptor trafficking) alterations or to both? Studies aimed to
clarify such questions at high spatiotemporal resolution will
undoubtedly provide key insights into the roles of actin
cytoskeleton in memory and will afford insight into cellular
events underpinning memory formation and greatly contribute to
a better elucidation of the intricate molecular and cellular
processes governing memory formation.
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Please cite this article in press as: Lamprecht, R., The actin cytoskeleton in memory formation. Prog. Neurobiol. (2014), http://dx.doi.org/
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