knafo and esteban con

CONEUR-1047; NO. OF PAGES 7

Common pathways for growth and for plasticityShira Knafo and Jose A Esteban

Available online at www.sciencedirect.com

Cell growth and differentiation in developing tissues are, at first

impression, quite different endeavors from readjusting synaptic

strength during activity-dependent synaptic plasticity in mature

neurons. Nevertheless, it is becoming increasingly clear that

these two distinct processes share multiple intracellular

signaling events. How these common pathways result in cell

division (during proliferation), large-scale cellular remodeling

(during differentiation) or synapse-specific changes (during

synaptic plasticity) is only starting to be elucidated. Here we

review the latest findings on two prototypical examples of these

shared mechanisms: the Ras-PI3K pathway and the

intracellular signaling elicited by neural cell adhesion molecules

interacting with growth factor receptors.

Address

Centro de Biologıa Molecular ‘‘Severo Ochoa’’ (CSIC-UAM), Nicolas

Cabrera 1, Madrid 28049, Spain

Corresponding authors: Knafo, Shira ([email protected]) and

Esteban, Jose A ([email protected])

Current Opinion in Neurobiology 2012, 22:1–7

This review comes from a themed issue on

Synaptic structure and function

Edited by Morgan Sheng and Antoine Triller

0959-4388/$ – see front matter

# 2012 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.conb.2012.02.008

IntroductionThere is growing evidence for a significant overlap be-

tween signaling pathways that execute cell growth and

differentiation programs in early development, and those

mediating synaptic plasticity later in postmitotic neurons

[1]. This notion is particularly evident for two major axes

of intracellular signaling, such as the PI3K-Akt-mTOR

and the Ras-MAPK pathways (see e.g. [2–4]). Indeed,

some prototypical oncogenes, such as several members of

the Ras family of small GTPases, are now well-estab-

lished mediators of synaptic plasticity signaling [5]. The

fact that similar intracellular machinery is used in differ-

ent cell types (or at different developmental stages) for

different purposes is not particularly new or surprising.

For example, at a basic cell biology level, the same type of

membrane transactions may operate for endocrine cells to

secrete hormones, for neurons to release neurotransmitter

or for a migrating cell to add patches of plasma membrane

in specific directions. Nevertheless, the question still

Please cite this article in press as: Knafo S, Esteban JA. Common pathways for growth and for

www.sciencedirect.com

remains as to how signaling pathways instructing growth

and differentiation switch their output to drive changes in

synaptic strength during plasticity. Are these pathways

essentially wired in the same manner, just producing

different results because of changing cellular constraints?

Or is a completely different repertoire of downstream

effectors recruited at different developmental stages?

And considering upstream triggering events, how does

the induction of activity-dependent synaptic plasticity

converge into similar pathways as those initiated by

extrinsic growth and survival signals? To address these

questions, we will consider two examples from recent

literature: the signaling pathways driven by phosphoino-

sitide-3,4,5-trisphosphate (PIP3) and by neuronal cell

adhesion molecule-fibroblast growth factor receptor

(NCAM-FGFR), and their role in plasticity mechanisms

operating at the postsynaptic terminal.

PIP3-dependent synaptic plasticityThe PIP3 pathway is a critical regulator of cell growth,

differentiation, and survival in early developmental

stages [6]. PIP3 is formed from phosphoinositide-4,5-

bisphosphate (PIP2) by a family of enzymes known as

phosphoinositide-3-kinases (PI3Ks) [7]. The reverse

reaction is carried out by the lipid phosphatase PTEN

(phosphatase and homolog deleted on chromosome ten).

PI3K and PTEN are critical players in cellular growth and

tumor progression. Indeed, PTEN was originally ident-

ified as a tumor suppressor, because of its ability to

downregulate PIP3 levels [8]. This pathway is the key

mediator for the pleiotropic effects of multiple neurotro-

phins and growth factors, such as BDNF, NGF, and

others. These ligands bind to specific receptor tyrosine

kinases, which upon activation and transphosphorylation

at tyrosine residues, recruit PI3K via SH2 domain inter-

actions [9]. The recruitment and activation of PI3K, with

the concomitant synthesis of PIP3, is then typically

relayed via the Akt-mTOR axis to trigger specific pro-

grams of gene expression [10].

Nevertheless, it is now clear that the PI3K-PTEN tan-

dem also plays local roles in controlling synaptic strength

during plasticity events in mature, differentiated neurons.

In fact, PI3K has been shown to be constitutively loca-

lized at synapses, by means of a direct interaction be-

tween its p85 subunit and AMPA receptors (AMPARs)

[11]. The activity of PI3K and the availability of PIP3 are

required for the delivery of new AMPARs into synapses in

response to NMDA receptor (NMDAR) activation [11],

and for the maintenance of AMPAR clustering on the

synaptic membrane [12�]. However, it has been very

challenging to identify downstream effectors of these

plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008


http://dx.doi.org/10.1016/j.conb.2012.02.008

mailto:[email protected]

mailto:[email protected]


http://www.sciencedirect.com/science/journal/09594388

2 Synaptic structure and function


signaling molecules that directly connect with the regu-

lation of synaptic strength. On the one hand, canonical

downstream signaling from PIP3 is likely involved, since

Akt activation and GSK3b inhibition are required for

efficient LTP expression [13]. On the other hand, direct

effects of PIP3 on the synaptic scaffold cannot be

excluded, since multiple PDZ domains have phosphoi-

nositide binding capabilities [14]. Indeed, PIP3 depletion

reduces the accumulation of PSD-95 at spines [12�], and

PI3K activation (in this case upon BDNF stimulation)

triggers the mobilization of PSD-95 in dendrites [15].

Additionally, PIP3 regulates the activity of multiple Rac

and Rho effectors [16]. In this manner, it may play

important (and complex) functions in the remodeling

of the actin cytoskeleton during synaptic plasticity.

Analogous to the connection between PIP3 formation and

synaptic potentiation, PIP3 turnover by the lipid phos-

phatase PTEN has been linked to synaptic depression

[17��,18]. Thus, PTEN is recruited to the postsynaptic

complex in a PDZ-dependent manner in response to

NMDAR activation. Upon synaptic recruitment, the cat-

alytic activity of PTEN is required for NMDAR-depend-

ent long-term depression (LTD), but not for other forms

of synaptic plasticity, such as metabotropic glutamate

receptor (mGluR)-dependent LTD or LTP [17��].Similar to the rationale for PI3K and LTP, the role of

PTEN in LTD may involve canonical PIP3 signaling (in

this case via Akt inactivation and GSK3b activation [13])

and/or direct effects from phosphoinositide metabolism.

It is important to keep in mind that PTEN’s action may

rely on the local depletion of PIP3, with the subsequent

removal of synaptic AMPARs [12�], but also on the local

production of PIP2 upon dephosphorylation of PIP3. PIP2

is a recruitment factor for multiple endocytic proteins,

such as dynein and clathrin adaptors [19], and in this

manner may regulate AMPAR endocytosis [20]. In fact,

the PIP2 synthesizing enzyme PIP5Kg661, associates

with the endocytic machinery at postsynaptic sites in

response to NMDAR activation, and its kinase activity

is required for NMDAR-dependent LTD [21��]. In

addition, PIP2 availability is important for LTD as a

substrate for further enzymatic turnover by phospholipase

C [22]. These observations underscore the complexities

of phosphoinositide metabolism, where turnover of one

phosphoinositide species will generate potential sub-

strates for further downstream signaling.

It is also important to avoid the oversimplification that

PIP2 > PIP3 metabolism favors synaptic potentiation,

whereas the converse reaction favors depression. PI3Ks

are a complex family of kinases with multiple isoforms

and regulatory subunits [7]. Neurons express many of

them, which are likely to have specialized functions. As a

testimony to this cautionary note, it has been recently

reported that genetic deletion of PI3Kg (which is specifi-

cally expressed in the brain, immune and cardiovascular



systems) impairs NMDAR-dependent LTD without

altering LTP or mGluR-dependent LTD [23�].

Upstream regulators. The antagonism of Rasand Rap signalingWhat would be the initiating events for the engagement

of PI3K and PTEN in synaptic plasticity? As mentioned

earlier, neurotrophins and related growth factors are

canonical upstream initiators of this pathway during cen-

tral nervous system development. There is also abundant

literature on the effects of BDNF on synaptic plasticity

and cognition in adult animals [2]. In fact, BDNF can

trigger AMPAR synthesis and delivery into synapses in

differentiated neurons [24,25]. Nevertheless, we may

expect that neurotrophin-independent mechanisms are

also at play, particularly for early phases of synaptic

plasticity (E-LTP, E-LTD), which do not require new

protein synthesis [26].

Some of the most paradigmatic forms of postsynaptic

plasticity require NMDAR activation (NMDAR-depend-

ent LTP and LTD). Therefore, one could expect that

NMDARs will be able to trigger the PIP3 pathway in

these forms of plasticity. Indeed, the connection between

NMDARs and PIP3 can be established by piecing

together multiple biochemical and physiological evi-

dences, mostly pointing to the role of the Ras–Rap

GTPases as signal transducers for synaptic plasticity.

The general scheme is depicted in Figure 1, and the

experimental evidence summarized as follows. Calcium

entry via NMDARs is able to produce local and transient

activation of Ras at spines [27��], possibly mediated by

calcium-dependent Ras activators, such as the guanine

nucleotide exchange factors Ras-GRF1 and 2, which are

expressed preferentially in adult neurons [28]. In fact,

Ras-GRF1 directly interacts with NMDARs [29], and

genetic deletions of Ras-GRF1 or 2 differentially alter

NMDAR-dependent synaptic plasticity [30]. Negative

regulation of Ras by GTPase activating proteins (GAPs)

is also likely to be important for synaptic function. Thus,

mutations in the Ras GAPs neurofibromin (NF1) [31] and

SynGap [32] are associated to cognitive dysfunction in

humans.

Ras is a central signaling hub for the activation of many

PI3K isoforms [33]. Interestingly, Ras may differentially

activate PI3K or mitogen-activated protein kinase

(MAPK), potentially providing further specificity (and

versatility) to Ras-mediated, NMDAR-dependent synap-

tic plasticity. In the case of LTP, it is known that both

pathways may be activated by Ras in an NMDAR-de-

pendent manner. In fact, it has been shown that Ras-

activated PI3K and MAPK pathways mediate the synap-

tic delivery of different populations of AMPARs [34]. In

agreement with this interpretation, a dominant negative

form of Ras strongly blocks AMPAR surface delivery




Common pathways for growth and for plasticity Knafo and Esteban 3


Figure 1

NMDAR AMPARStgz

PTEN

endocytosisPIP2

PIP3

PI3K

AKt

+

–

LTP

LTD GSK3β

ERKMAPK

PSD95

Ras•GTP

Rap•GTP

Ras-GRF

Ca2+

Current Opinion in Neurobiology

Simplified scheme for the activation and downstream actions of the PIP3

pathway during synaptic plasticity. Upon opening of NMDARs, calcium-

sensitive Ras-GRFs nucleotide exchange factors lead to the formation of

active Ras, with the concomitant activation of PI3K. This enzyme

catalyzes the formation of PIP3, which in turn may act directly on

receptor scaffolding complexes, or indirectly, via Akt activation and

GSK3b inhibition. Ras also activates ERK–MAPK downstream signaling.

These pathways jointly lead to LTP expression. Alternatively, NMDAR

can lead to the activation of Rap, for LTD expression. PTEN catalyzes

the turnover of PIP3 to form PIP2. Inhibition of Akt and activation of

GSK3b will favor LTD induction. In addition, formation of PIP2 will lead to

the recruitment of endocytic factors and the internalization of AMPARs

for LTD expression.

during LTP, whereas MAPK inhibition only produces a

partial reduction [35].

Rap proteins are small GTPases closely related to Ras.

They are often related to the control of cellular adhesion

and polarity [36], and were originally described to

antagonize the cell proliferation activity induced by

Ras [37]. Interestingly, in neuronal cells, Ras and Rap

also seem to play antagonistic roles, by modulating LTP

and LTD, respectively [38]. The connection between

NMDAR opening and Rap activation during synaptic

plasticity is more uncertain, but it is likely to involve

synaptically localized Rap regulators, such as SPAR [39]

or SynGap (which has GAP activity for both Rap and Ras

[40]). Regardless of the specific intermediate steps, it has

been shown that NMDAR activation does lead to an

increase in Rap-GTP formation and reduced AMPAR

presence at synapses [41]. In addition, Rap may partici-

pate in other forms of AMPAR removal and synaptic

depression, such as those mediated by cAMP signaling

[42�,43].

This antagonistic, but often times overlapping signaling

mediated by Ras and Rap, is itself modulated by the

regulation of their effectors. For example, it has been

recently shown that polo-like kinase 2 (Plk2) is able to



phosphorylate multiple Ras and Rap effectors, and in this

manner it may coordinate their activation and down-

stream signaling during structural and functional

plasticity [44��] (see also [45] for a recent review on small

GTPase signaling in dendritic spines).

NCAM/FGFR signaling pathwayCell adhesion molecules are well-known effectors of

neuronal development and synaptogenesis [46], because

of their ability to mediate cell-to-cell communication and

interactions with the extracellular matrix. They also

promote intracellular signaling cascades, particularly

upon interaction and co-activation with growth factor

receptors [47]. Neural cell adhesion molecule (NCAM)

is a cell-surface glycoprotein with an extracellular portion

containing five immunoglobulin (Ig)-like modules fol-

lowed by two fibronectin type III (F3) modules. NCAM

is involved in homophilic interactions and in heterophilic

binding to a variety of membrane proteins and com-

ponents of the extracellular matrix [48]. Among the

heterophilic partners of NCAM are the fibroblast growth

factor receptors (FGFR1–4) that contain three Ig-like

modules, a single transmembrane domain, and a split

tyrosine-kinase domain. All FGFR isoforms, except for

FGFR4, are involved in a direct interaction with NCAM

[49] through its F3 module ectodomain [50,51]. When

NCAM mediates cell–cell adhesion (trans-homophilic

binding), it clusters into ‘zipper’-like arrays that lead to

clustering of FGFRs [52]. The resulted increase in the

local concentration of FGFRs triggers a direct receptor–receptor dimerization, autophosphorylation [53], and acti-

vation [54]. This activation results in the recruitment and

stimulation of specific effectors that, in turn, trigger a set

of signaling pathways [55] that can be enhanced by

NCAM polysialylation [56] and mediate many of the

functions of NCAM. Among these signaling pathways

are the FGF receptor substrate 2a (FRS2a), phospho-

lipase-Cg (PLCg), and Src homologous and collagen A

(ShcA) that function as links to MAPK and the PI3K

pathways [57,58].

NCAM/FGFR in synaptic plasticity andcognitionNCAM activity is essential for early synaptogenesis and

synaptic maturation [46]. In addition, NCAM influences

the strength of excitatory synapses in an activity-depend-

ent manner [59] and therefore can regulate synaptic

plasticity [60]. The elucidation of the three-dimensional

structure of the extracellular domains of NCAM made it

possible to design synthetic ligands, which mimic various

functions of NCAM. These peptides have contributed

greatly to the elucidation of NCAM’s role in synaptic

functions [61]. The most studied synthetic NCAM-

mimetic peptide, termed FGLoop (FGL) was engineered

specifically to mimic the functional interaction between

NCAM and FGFR [62]. FGL encompasses the inter-

action domain of NCAM with FGFR: F and G b-strands






and the interconnecting loop of the second F3 module of

NCAM. Similarly to NCAM, FGL was found to elicit

FGFR-mediated signaling [63] and to induce neuritogen-

esis and survival in neuronal cultures [64].

One important advantage of these mimetic peptides is

that intracellular signaling can be triggered acutely in

adult animals or brain tissue to assess the role of these

pathways in synaptic plasticity, while bypassing their

function in neuronal development. Thus, it has been

shown that FGL treatment enhances dentate gyrus

[65�] and CA3-to-CA1 [66��] LTP. Importantly, in vivoadministration of FGL also improved spatial and social

memory retention in rats [62,66��,67]. FGL also prevents

cognitive impairment induced by stress [68,69] and by

oligomeric b-amyloid [70]. Therefore, FGL acts as an

efficient cognitive enhancer, by engaging NCAM-FGFR-

related signaling.

As mentioned above, NCAM-FGFR intracellular sig-

naling may be relayed via PLC, MAPK, and PI3K path-

ways. Given this complexity, what are the relevant

mediators and synaptic mechanisms for their effect on

plasticity and cognition in mature animals? This has also

been investigated by means of the FGL peptide. We have

recently found that FGL acts by facilitating the delivery


Figure 2

NCAM FGFR

NMDAR

PI3KAkt

mTOR

gene expressioncell remodeling

RasERK

MAPK

PLCPKC +

AMPARStgz

PSD95

CaMKII

Ca2+

Current Opinion in Neurobiology

Facilitation of AMPAR synaptic delivery by NCAM-FGFR signaling.

Heterophilic interactions between the extracellular immunoglobulin (Ig)-

like domains of NCAM with FGFR lead to the activation of three major

signaling axes: ERK–MAPK, PI3K-AKT-mTOR, and PLC-PKC. The two

former ones are critical for changes in gene expression leading to cell

remodeling, and are involved in several forms of synaptic plasticity. The

PKC pathway is uniquely required for the facilitation of the synaptic

delivery of AMPARs during NMDAR-dependent LTP. This process is

accompanied by a long-lasting activation of CaMKII.


of new AMPA receptors into synapses, in response to

NMDAR activation. This is accompanied by enhanced

NMDAR-dependent LTP [66��]. Interestingly, these

effects are long-lasting. That is, facilitated AMPAR deliv-

ery and enhanced LTP persist at least for two days after

FGL is removed. As for the signaling pathways involved,

we observed that FGL triggers an initial PKC activation,

which is then followed by persistent CaMKII activation.

Inhibition of PKC activity during FGL administration

blocks the synaptic and cognitive effects of FGL, whereas

PI3K and MAPK inhibitors do not [66��]. Therefore, it

appears that PKC initiates a cascade of signaling events,

which are then translated into a persistent CaMKII

activity, which is probably responsible for the long-lasting

synaptic and cognitive effects of FGL. The mechanism(s)

linking FGL-triggered PKC activation to the facilitation

of LTP and AMPAR synaptic delivery still remain to be

determined. Nevertheless, it seems that only a subset of

the potential signaling events elicited by NCAM-FGFR

are dedicated to synaptic plasticity modification

(Figure 2).

ConclusionsAt least with respect to postsynaptic forms of plasticity,

there appears to be a straightforward route linking

NMDAR activation to the PIP3 pathway: calcium entry,

activation of Ras-GRF nucleotide exchange factors, for-

mation of Ras-GTP, subsequent PI3K activation, and

PIP3 formation. PTEN would not simply act as an oppos-

ing force to this flow, but it would play specific functions

during LTD. Nevertheless, this scenario is deceivingly

simple (and linear), considering the dense overlap and

feedback mechanisms operating on almost all the

elements of this route. It is also still unclear how these

mechanisms interplay with the ‘canonical’ LTP and

LTD signaling, particularly CaMKII and PP1/PP2B,

respectively. This integration will probably require more

direct and incisive approaches to manipulate and image

these pathways acting jointly at postsynaptic terminals.

As for the synaptic functions of growth factor receptors,

particularly NCAM-FGFR signaling, we are still far from

having a step-by-step mechanism as the one described

above. Nevertheless, this pathway is able to modulate

synaptic plasticity at mature CA3-to-CA1 synapses in a

very distinct manner. In this case, activation of the PLC-

PKC pathway sensitizes NMDAR-dependent synaptic

potentiation in a long-lasting manner, by facilitating

the synaptic delivery of AMPARs. From a mechanistic

point of view, there are several missing pieces of infor-

mation, particularly, the direct targets of PKC mediating

this effect. As described here, this pathway would not be

an integral part of the synaptic plasticity process, but

rather a modulator of its efficacy. Obviously, this obser-

vation does not detract from its relevance. In fact, the

molecular dissection of these intertwined signaling path-

ways is of the outmost importance, considering that most






physiological (and pathological) variations in cognitive

function are likely due to modulatory influences on ‘core’

synaptic plasticity mechanisms.

References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

� of special interest

�� of outstanding interest

1. Frank CL, Tsai LH: Alternative functions of core cell cycleregulators in neuronal migration, neuronal maturation, andsynaptic plasticity. Neuron 2009, 62:312-326.

2. Yoshii A, Constantine-Paton M: Postsynaptic BDNF-TrkBsignaling in synapse maturation, plasticity, and disease. DevNeurobiol 2010, 70:304-322.

3. Thomas GM, Huganir RL: MAPK cascade signalling andsynaptic plasticity. Nat Rev Neurosci 2004, 5:173-183.

4. Sweatt JD: Mitogen-activated protein kinases in synapticplasticity and memory. Curr Opin Neurobiol 2004, 14:311-317.

5. Ye X, Carew TJ: Small G protein signaling in neuronal plasticityand memory formation: the specific role of ras family proteins.Neuron 2010, 68:340-361.

6. Cantley LC: The phosphoinositide 3-kinase pathway. Science2002, 296:1655-1657.

7. Wymann MP, Pirola L: Structure and function ofphosphoinositide 3-kinases. Biochim Biophys Acta 1998,1436:127-150.

8. Maehama T, Dixon JE: PTEN: a tumour suppressor thatfunctions as a phospholipid phosphatase. Trends Cell Biol1999, 9:125-128.

9. Reichardt LF: Neurotrophin-regulated signalling pathways.Philos Trans R Soc Lond B: Biol Sci 2006, 361:1545-1564.

10. Ma XM, Blenis J: Molecular mechanisms of mTOR-mediatedtranslational control. Nat Rev Mol Cell Biol 2009, 10:307-318.

11. Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D’Souza S,Wong TP, Taghibiglou C, Lu J et al.: Activation of PI3-kinase isrequired for AMPA receptor insertion during LTP of mEPSCs incultured hippocampal neurons. Neuron 2003, 38:611-624.

12.�

Arendt KL, Royo M, Fernandez-Monreal M, Knafo S, Petrok CN,Martens JR, Esteban JA: PIP3 controls synaptic function bymaintaining AMPA receptor clustering at the postsynapticmembrane. Nat Neurosci 2010, 13:36-44.

Using electrophysiological and imaging techniques, the authors describespecific functions of PIP3 at the postsynaptic terminal, which involve themaintenance of AMPARs at the synaptic membrane.

13. Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E,Wu D, Saule E, Bouschet T et al.: LTP inhibits LTD in thehippocampus via regulation of GSK3beta. Neuron 2007,53:703-717.

14. Zimmermann P: The prevalence and significance of PDZdomain–phosphoinositide interactions. Biochim Biophys Acta2006, 1761:947-956.

15. Yoshii A, Constantine-Paton M: BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDAreceptor activation. Nat Neurosci 2007, 10:702-711.

16. Yin HL, Janmey PA: Phosphoinositide regulation of the actincytoskeleton. Annu Rev Physiol 2003, 65:761-789.

17.��

Jurado S, Benoist M, Lario A, Knafo S, Petrok CN, Esteban JA:PTEN is recruited to the postsynaptic terminal for NMDAreceptor-dependent long-term depression. EMBO J 2010,29:2827-2840.

PTEN is a major regulator of cellular and organ growth during develop-ment. In this work the authors dissect distinct functions of PTEN onmature synapses, particularly as a mediator of long-term depression(LTD).



18. Wang Y, Cheng A, Mattson MP: The PTEN phosphatase isessential for long-term depression of hippocampal synapses.Neuromol Med 2006, 8:329-336.

19. Di Paolo G, De Camilli P: Phosphoinositides in cell regulationand membrane dynamics. Nature 2006, 443:651-657.

20. Gong LW, De Camilli P: Regulation of postsynaptic AMPAresponses by synaptojanin 1. Proc Natl Acad Sci U S A 2008,105:17561-17566.

21.��

Unoki T, Matsuda S, Kakegawa W, Van NT, Kohda K, Suzuki A,Funakoshi Y, Hasegawa H, Yuzaki M, Kanaho Y: NMDA receptor-mediated PIP5K activation to produce PI(4,5)P(2) is essentialfor AMPA receptor endocytosis during LTD. Neuron 2012,73:135-148.

Using a gene knockdown approach, the authors demonstrate that PIP2formation is regulated in response to NMDAR activation, and this processis critical for the internalization of AMPARs during LTD.

22. Horne EA, Dell’Acqua ML: Phospholipase C is required forchanges in postsynaptic structure and function associatedwith NMDA receptor-dependent long-term depression. JNeurosci 2007, 27:3523-3534.

23.�

Kim JI, Lee HR, Sim SE, Baek J, Yu NK, Choi JH, Ko HG, Lee YS,Park SW, Kwak C et al.: PI3Kgamma is required for NMDAreceptor-dependent long-term depression and behavioralflexibility. Nat Neurosci 2011, 14:1447-1454.

Using a new mouse knockout model, the authors identify a specific PIP3

synthesizing enzyme (PI3Kgamma) as required for LTD and specificcognitive functions.

24. Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS,Backos DS, Carvalho AL, Esteban JA, Duarte CB: Brain-derivedneurotrophic factor regulates the expression and synapticdelivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits in hippocampal neurons. JBiol Chem 2007, 282:12619-12628.

25. Li X, Wolf ME: Brain-derived neurotrophic factor rapidlyincreases AMPA receptor surface expression in rat nucleusaccumbens. Eur J Neurosci 2011, 34:190-198.

26. Frey U, Krug M, Reymann KG, Matthies H: Anisomycin, aninhibitor of protein synthesis, blocks late phases of LTPphenomena in the hippocampal CA1 region in vitro. Brain Res1988, 452:57-65.

27.��

Harvey CD, Yasuda R, Zhong H, Svoboda K: The spread of Rasactivity triggered by activation of a single dendritic spine.Science 2008, 321:136-140.

In this work, using multiphoton fluorescence microscopy and focalsynaptic stimulation, the authors determine the temporal and spatialdetails of Ras activation upon NMDAR opening during LTP.

28. Feig LA: Regulation of neuronal function by Ras-GRFexchange factors. Genes Cancer 2011, 2:306-319.

29. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R,Pellegrino C, Ben-Ari Y, Clapham DE, Medina I: The NMDAreceptor is coupled to the ERK pathway by a direct interactionbetween NR2B and RasGRF1. Neuron 2003, 40:775-784.

30. Li S, Tian X, Hartley DM, Feig LA: Distinct roles for Ras-guaninenucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in theinduction of long-term potentiation and long-term depression.J Neurosci 2006, 26:1721-1729.

31. Shilyansky C, Lee YS, Silva AJ: Molecular and cellularmechanisms of learning disabilities: a focus on NF1. Annu RevNeurosci 2010, 33:221-243.

32. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y,Pellerin S, Dobrzeniecka S, Cote M, Perreau-Linck E, Carmant Let al.: Mutations in SYNGAP1 in autosomal nonsyndromicmental retardation. N Engl J Med 2009, 360:599-605.

33. Castellano E, Downward J: RAS interaction with PI3K: morethan just another effector pathway. Genes Cancer 2011, 2:261-274.

34. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V,van Aelst L, Zhu JJ: State-dependent Ras signaling and AMPAreceptor trafficking. Genes Dev 2005, 19:2000-2015.






35. Patterson MA, Szatmari EM, Yasuda R: AMPA receptors areexocytosed in stimulated spines and adjacent dendrites in aRas-ERK-dependent manner during long-term potentiation.Proc Natl Acad Sci U S A 2010, 107:15951-15956.

36. Bos JL: Linking Rap to cell adhesion. Curr Opin Cell Biol 2005,17:123-128.

37. Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M: A ras-related gene with transformation suppressor activity. Cell1989, 56:77-84.

38. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R: Ras and Rapcontrol AMPA receptor trafficking during synaptic plasticity.Cell 2002, 110:443-455.

39. Pak DT, Yang S, Rudolph-Correia S, Kim E, Sheng M: Regulationof dendritic spine morphology by SPAR, a PSD-95-associatedRapGAP. Neuron 2001, 31:289-303.

40. Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE:SynGAP-MUPP1-CaMKII synaptic complexes regulate p38MAP kinase activity and NMDA receptor-dependentsynaptic AMPA receptor potentiation. Neuron 2004,43:563-574.

41. Xie Z, Huganir RL, Penzes P: Activity-dependent dendritic spinestructural plasticity is regulated by small GTPase Rap1 and itstarget AF-6. Neuron 2005, 48:605-618.

42.�

Woolfrey KM, Srivastava DP, Photowala H, Yamashita M,Barbolina MV, Cahill ME, Xie Z, Jones KA, Quilliam LA, Prakriya Met al.: Epac2 induces synapse remodeling and depression andits disease-associated forms alter spines. Nat Neurosci 2009,12:1275-1284.

This study provides an upstream activator and a downstream mechan-istic link for the role of Rap in synaptic depression and spine remodel-ing.

43. Ster J, de Bock F, Bertaso F, Abitbol K, Daniel H, Bockaert J,Fagni L: Epac mediates PACAP-dependent long-termdepression in the hippocampus. J Physiol 2009,587:101-113.

44.��

Lee KJ, Lee Y, Rozeboom A, Lee JY, Udagawa N, Hoe HS, Pak DT:Requirement for Plk2 in orchestrated ras and rap signaling,homeostatic structural plasticity, and memory. Neuron 2011,69:957-973.

This work illustrates how Ras and Rap is integrated at synaptic terminals,by means of a specific kinase that phosphorylates multiple Ras and Rapregulators.

45. Kennedy MB, Beale HC, Carlisle HJ, Washburn LR: Integration ofbiochemical signalling in spines. Nat Rev Neurosci 2005, 6:423-434.

46. Washbourne P, Dityatev A, Scheiffele P, Biederer T, Weiner JA,Christopherson KS, El-Husseini A: Cell adhesion molecules insynapse formation. J Neurosci 2004, 24:9244-9249.

47. Skaper SD, Moore SE, Walsh FS: Cell signalling cascadesregulating neuronal growth-promoting and inhibitory cues.Prog Neurobiol 2001, 65:593-608.

48. Maness PF, Schachner M: Neural recognition molecules of theimmunoglobulin superfamily: signaling transducers of axonguidance and neuronal migration. Nat Neurosci 2007,10:19-26.

49. Christensen C, Berezin V, Bock E: Neural cell adhesion moleculedifferentially interacts with isoforms of the fibroblast growthfactor receptor. Neuroreport 2011, 22:727-732.

50. Hansen SM, Li S, Bock E, Berezin V: Synthetic NCAM-derivedligands of the fibroblast growth factor receptor. Adv Exp MedBiol 2010, 663:355-372.

51. Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N,Soroka V, Pedersen N, Tsetlin V, Poulsen FM, Berezin V et al.:Structural basis for a direct interaction between FGFR1 andNCAM and evidence for a regulatory role of ATP. Structure2003, 11:691-701.

52. Kiselyov VV, Soroka V, Berezin V, Bock E: Structural biology ofNCAM homophilic binding and activation of FGFR. JNeurochem 2005, 94:1169-1179.



53. Mohammadi M, Olsen SK, Ibrahimi OA: Structural basis forfibroblast growth factor receptor activation. Cytokine GrowthFactor Rev 2005, 16:107-137.

54. Kochoyan A, Poulsen FM, Berezin V, Bock E, Kiselyov VV:Structural basis for the activation of FGFR by NCAM. ProteinSci 2008, 10:1698-1705.

55. Beenken A, Mohammadi M: The FGF family: biology,pathophysiology and therapy. Nat Rev Drug Discov 2009, 8:235-253.

56. Li J, Dai G, Cheng YB, Qi X, Geng MY: Polysialylation promotesneural cell adhesion molecule-mediated cell migration in afibroblast growth factor receptor-dependent manner, butindependent of adhesion capability. Glycobiology 2011,21:1010-1018.

57. Eswarakumar VP, Lax I, Schlessinger J: Cellular signaling byfibroblast growth factor receptors. Cytokine Growth Factor Rev2005, 16:139-149.

58. Dailey L, Ambrosetti D, Mansukhani A, Basilico C: Mechanismsunderlying differential responses to FGF signaling. CytokineGrowth Factor Rev 2005, 16:233-247.

59. Dityatev A, Dityateva G, Schachner M: Synaptic strength as afunction of post-versus presynaptic expression of theneural cell adhesion molecule NCAM. Neuron 2000,26:207-217.

60. Muller D, Wang C, Skibo G, Toni N, Cremer H, Calaora V,Rougon G, Kiss JZ: PSA NCAM is required for activity-inducedsynaptic plasticity. Neuron 1996, 17:413-422.

61. Berezin V, Bock E: NCAM mimetic peptides: pharmacologicaland therapeutic potential. J Mol Neurosci 2004,22:33-39.

62. Cambon K, Hansen SM, Venero C, Herrero AI, Skibo G, Berezin V,Bock E, Sandi C: A synthetic neural cell adhesion moleculemimetic peptide promotes synaptogenesis, enhancespresynaptic function, and facilitates memory consolidation. JNeurosci 2004, 24:4197-4204.

63. Chen Y, Li S, Berezin V, Bock E: The fibroblast growth factorreceptor (FGFR) agonist FGF1 and the neural cell adhesionmolecule-derived peptide FGL activate FGFR substrate2alpha differently. J Neurosci Res 2010, 88:1882-1889.

64. Neiiendam JL, Kohler LB, Christensen C, Li S, Pedersen MV,Ditlevsen DK, Kornum MK, Kiselyov VV, Berezin V, Bock E: AnNCAM-derived FGF-receptor agonist, the FGL-peptide,induces neurite outgrowth and neuronal survival in primary ratneurons. J Neurochem 2004, 91:920-935.

65.�

Dallerac G, Zerwas M, Novikova T, Callu D, Leblanc-Veyrac P,Bock E, Berezin V, Rampon C, Doyere V: The neural celladhesion molecule-derived peptide FGL facilitates long-termplasticity in the dentate gyrus in vivo. Learn Mem 2011, 18:306-313.

Using electrophysiological techniques in awake, freely moving animals,the authors determine that the NCAM-mimetic peptide FGL produces along-lasting enhancement of synaptic plasticity.

66.��

Knafo S, Venero C, Sanchez-Puelles C, Pereda-Perez I, Franco A,Sandi C, Suarez LM, Solis JM, Alonso-Nanclares L, Martin EDet al.: Facilitation of AMPA receptor synaptic delivery as amolecular mechanism for cognitive enhancement. PLoS Biol2012, 2 doi: 10.1371/journal.pbio.1001262.

Using a combination of electrophysiological, imaging, and behavioraltechniques, the authors dissect the signaling pathways and synapticmechanisms by which FGL enhances cognitive performance in spatiallearning and memory tasks.

67. Secher T, Novitskaia V, Berezin V, Bock E, Glenthoj B,Klementiev B: A neural cell adhesion molecule-derivedfibroblast growth factor receptor agonist, the FGL-peptide,promotes early postnatal sensorimotor development andenhances social memory retention. Neuroscience 2006,141:1289-1299.

68. Borcel E, Perez-Alvarez L, Herrero AI, Brionne T, Varea E,Berezin V, Bock E, Sandi C, Venero C: Chronic stress inadulthood followed by intermittent stress impairs spatialmemory and the survival of newborn hippocampal cells in



http://dx.doi.org/10.1371/journal.pbio.1001262




aging animals: prevention by FGL, a peptide mimetic of neuralcell adhesion molecule. Behav Pharmacol 2008, 19:41-49.

69. Bisaz R, Schachner M, Sandi C: Causal evidence for theinvolvement of the neural cell adhesion molecule. NCAM, inchronic stress-induced cognitive impairments. Hippocampus2011, 21:56-71.



70. Klementiev B, Novikova T, Novitskaya V, Walmod PS,Dmytriyeva O, Pakkenberg B, Berezin V, Bock E: A neural celladhesion molecule-derived peptide reducesneuropathological signs and cognitive impairment induced byAbeta25-35. Neuroscience 2007, 145:209-224.




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