1) The document discusses common intracellular signaling pathways that are involved in both growth/differentiation processes early in development and synaptic plasticity in mature neurons. 2) Two examples are described in detail: the Ras-PI3K pathway and signaling elicited by neural cell adhesion molecules (NCAMs) interacting with growth factor receptors. 3) For the Ras-PI3K pathway, calcium entry via NMDA receptors can activate Ras, which then activates PI3K to produce PIP3 and drive LTP. Alternatively, NMDA receptors can activate Rap proteins to induce PTEN, reduce PIP3, and drive LTD.

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Common pathways for growth and for plasticity
´
Shira Knafo and Jose A Esteban
Cell growth and differentiation in developing tissues are, at first remains as to how signaling pathways instructing growth
impression, quite different endeavors from readjusting synaptic and differentiation switch their output to drive changes in
strength during activity-dependent synaptic plasticity in mature synaptic strength during plasticity. Are these pathways
neurons. Nevertheless, it is becoming increasingly clear that essentially wired in the same manner, just producing
these two distinct processes share multiple intracellular different results because of changing cellular constraints?
signaling events. How these common pathways result in cell Or is a completely different repertoire of downstream
division (during proliferation), large-scale cellular remodeling effectors recruited at different developmental stages?
(during differentiation) or synapse-specific changes (during And considering upstream triggering events, how does
synaptic plasticity) is only starting to be elucidated. Here we the induction of activity-dependent synaptic plasticity
review the latest findings on two prototypical examples of these converge into similar pathways as those initiated by
shared mechanisms: the Ras-PI3K pathway and the extrinsic growth and survival signals? To address these
intracellular signaling elicited by neural cell adhesion molecules questions, we will consider two examples from recent
interacting with growth factor receptors. literature: the signaling pathways driven by phosphoino-
sitide-3,4,5-trisphosphate (PIP3) and by neuronal cell
Address adhesion molecule-fibroblast growth factor receptor
´ ´
Centro de Biologıa Molecular ‘‘Severo Ochoa’’ (CSIC-UAM), Nicolas (NCAM-FGFR), and their role in plasticity mechanisms
Cabrera 1, Madrid 28049, Spain
operating at the postsynaptic terminal.
Corresponding authors: Knafo, Shira (sknafo@cbm.uam.es) and
´
Esteban, Jose A (jaesteban@cbm.uam.es) PIP3-dependent synaptic plasticity
The PIP3 pathway is a critical regulator of cell growth,
differentiation, and survival in early developmental
Current Opinion in Neurobiology 2012, 22:1–7 stages [6]. PIP3 is formed from phosphoinositide-4,5-
This review comes from a themed issue on
bisphosphate (PIP2) by a family of enzymes known as
Synaptic structure and function phosphoinositide-3-kinases (PI3Ks) [7]. The reverse
Edited by Morgan Sheng and Antoine Triller 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
0959-4388/$ – see front matter tumor progression. Indeed, PTEN was originally ident-
# 2012 Elsevier Ltd. All rights reserved. ified as a tumor suppressor, because of its ability to
DOI 10.1016/j.conb.2012.02.008
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
Introduction kinases, which upon activation and transphosphorylation
There is growing evidence for a significant overlap be- at tyrosine residues, recruit PI3K via SH2 domain inter-
tween signaling pathways that execute cell growth and actions [9]. The recruitment and activation of PI3K, with
differentiation programs in early development, and those the concomitant synthesis of PIP3, is then typically
mediating synaptic plasticity later in postmitotic neurons relayed via the Akt-mTOR axis to trigger specific pro-
[1]. This notion is particularly evident for two major axes grams of gene expression [10].
of intracellular signaling, such as the PI3K-Akt-mTOR
and the Ras-MAPK pathways (see e.g. [2–4]). Indeed, Nevertheless, it is now clear that the PI3K-PTEN tan-
some prototypical oncogenes, such as several members of dem also plays local roles in controlling synaptic strength
the Ras family of small GTPases, are now well-estab- during plasticity events in mature, differentiated neurons.
lished mediators of synaptic plasticity signaling [5]. The In fact, PI3K has been shown to be constitutively loca-
fact that similar intracellular machinery is used in differ- lized at synapses, by means of a direct interaction be-
ent cell types (or at different developmental stages) for tween its p85 subunit and AMPA receptors (AMPARs)
different purposes is not particularly new or surprising. [11]. The activity of PI3K and the availability of PIP3 are
For example, at a basic cell biology level, the same type of required for the delivery of new AMPARs into synapses in
membrane transactions may operate for endocrine cells to response to NMDA receptor (NMDAR) activation [11],
secrete hormones, for neurons to release neurotransmitter and for the maintenance of AMPAR clustering on the
or for a migrating cell to add patches of plasma membrane synaptic membrane [12]. However, it has been very
in specific directions. Nevertheless, the question still challenging to identify downstream effectors of these
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2 Synaptic structure and function
signaling molecules that directly connect with the regu- systems) impairs NMDAR-dependent LTD without
lation of synaptic strength. On the one hand, canonical altering LTP or mGluR-dependent LTD [23].
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 Upstream regulators. The antagonism of Ras
effects of PIP3 on the synaptic scaffold cannot be and Rap signaling
excluded, since multiple PDZ domains have phosphoi- What would be the initiating events for the engagement
nositide binding capabilities [14]. Indeed, PIP3 depletion of PI3K and PTEN in synaptic plasticity? As mentioned
reduces the accumulation of PSD-95 at spines [12], and earlier, neurotrophins and related growth factors are
PI3K activation (in this case upon BDNF stimulation) canonical upstream initiators of this pathway during cen-
triggers the mobilization of PSD-95 in dendrites [15]. tral nervous system development. There is also abundant
Additionally, PIP3 regulates the activity of multiple Rac literature on the effects of BDNF on synaptic plasticity
and Rho effectors [16]. In this manner, it may play and cognition in adult animals [2]. In fact, BDNF can
important (and complex) functions in the remodeling trigger AMPAR synthesis and delivery into synapses in
of the actin cytoskeleton during synaptic plasticity. differentiated neurons [24,25]. Nevertheless, we may
expect that neurotrophin-independent mechanisms are
Analogous to the connection between PIP3 formation and also at play, particularly for early phases of synaptic
synaptic potentiation, PIP3 turnover by the lipid phos- plasticity (E-LTP, E-LTD), which do not require new
phatase PTEN has been linked to synaptic depression protein synthesis [26].
[17,18]. Thus, PTEN is recruited to the postsynaptic
complex in a PDZ-dependent manner in response to Some of the most paradigmatic forms of postsynaptic
NMDAR activation. Upon synaptic recruitment, the cat- plasticity require NMDAR activation (NMDAR-depend-
alytic activity of PTEN is required for NMDAR-depend- ent LTP and LTD). Therefore, one could expect that
ent long-term depression (LTD), but not for other forms NMDARs will be able to trigger the PIP3 pathway in
of synaptic plasticity, such as metabotropic glutamate these forms of plasticity. Indeed, the connection between
receptor (mGluR)-dependent LTD or LTP [17]. NMDARs and PIP3 can be established by piecing
Similar to the rationale for PI3K and LTP, the role of together multiple biochemical and physiological evi-
PTEN in LTD may involve canonical PIP3 signaling (in dences, mostly pointing to the role of the Ras–Rap
this case via Akt inactivation and GSK3b activation [13]) GTPases as signal transducers for synaptic plasticity.
and/or direct effects from phosphoinositide metabolism. The general scheme is depicted in Figure 1, and the
It is important to keep in mind that PTEN’s action may experimental evidence summarized as follows. Calcium
rely on the local depletion of PIP3, with the subsequent entry via NMDARs is able to produce local and transient
removal of synaptic AMPARs [12], but also on the local activation of Ras at spines [27], possibly mediated by
production of PIP2 upon dephosphorylation of PIP3. PIP2 calcium-dependent Ras activators, such as the guanine
is a recruitment factor for multiple endocytic proteins, nucleotide exchange factors Ras-GRF1 and 2, which are
such as dynein and clathrin adaptors [19], and in this expressed preferentially in adult neurons [28]. In fact,
manner may regulate AMPAR endocytosis [20]. In fact, Ras-GRF1 directly interacts with NMDARs [29], and
the PIP2 synthesizing enzyme PIP5Kg661, associates genetic deletions of Ras-GRF1 or 2 differentially alter
with the endocytic machinery at postsynaptic sites in NMDAR-dependent synaptic plasticity [30]. Negative
response to NMDAR activation, and its kinase activity regulation of Ras by GTPase activating proteins (GAPs)
is required for NMDAR-dependent LTD [21]. In is also likely to be important for synaptic function. Thus,
addition, PIP2 availability is important for LTD as a mutations in the Ras GAPs neurofibromin (NF1) [31] and
substrate for further enzymatic turnover by phospholipase SynGap [32] are associated to cognitive dysfunction in
C [22]. These observations underscore the complexities humans.
of phosphoinositide metabolism, where turnover of one
phosphoinositide species will generate potential sub- Ras is a central signaling hub for the activation of many
strates for further downstream signaling. PI3K isoforms [33]. Interestingly, Ras may differentially
activate PI3K or mitogen-activated protein kinase
It is also important to avoid the oversimplification that (MAPK), potentially providing further specificity (and
PIP2 PIP3 metabolism favors synaptic potentiation, versatility) to Ras-mediated, NMDAR-dependent synap-
whereas the converse reaction favors depression. PI3Ks tic plasticity. In the case of LTP, it is known that both
are a complex family of kinases with multiple isoforms pathways may be activated by Ras in an NMDAR-de-
and regulatory subunits [7]. Neurons express many of pendent manner. In fact, it has been shown that Ras-
them, which are likely to have specialized functions. As a activated PI3K and MAPK pathways mediate the synap-
testimony to this cautionary note, it has been recently tic delivery of different populations of AMPARs [34]. In
reported that genetic deletion of PI3Kg (which is specifi- agreement with this interpretation, a dominant negative
cally expressed in the brain, immune and cardiovascular form of Ras strongly blocks AMPAR surface delivery
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Common pathways for growth and for plasticity Knafo and Esteban 3
Figure 1 phosphorylate multiple Ras and Rap effectors, and in this
manner it may coordinate their activation and down-
NMDAR AMPAR stream signaling during structural and functional
Stgz
plasticity [44] (see also [45] for a recent review on small
GTPase signaling in dendritic spines).
PSD95
Ca2+
NCAM/FGFR signaling pathway
PTEN Cell adhesion molecules are well-known effectors of
Ras•GTP PIP3
Ras- neuronal development and synaptogenesis [46], because
GRF PI3K PIP2 endocytosis of their ability to mediate cell-to-cell communication and
+ interactions with the extracellular matrix. They also
ERK promote intracellular signaling cascades, particularly
LTP AKt
MAPK upon interaction and co-activation with growth factor
– receptors [47]. Neural cell adhesion molecule (NCAM)
Rap is a cell-surface glycoprotein with an extracellular portion
LTD GSK3β
•GTP containing five immunoglobulin (Ig)-like modules fol-
Current Opinion in Neurobiology lowed by two fibronectin type III (F3) modules. NCAM
is involved in homophilic interactions and in heterophilic
Simplified scheme for the activation and downstream actions of the PIP3 binding to a variety of membrane proteins and com-
pathway during synaptic plasticity. Upon opening of NMDARs, calcium- ponents of the extracellular matrix [48]. Among the
sensitive Ras-GRFs nucleotide exchange factors lead to the formation of heterophilic partners of NCAM are the fibroblast growth
active Ras, with the concomitant activation of PI3K. This enzyme
catalyzes the formation of PIP3, which in turn may act directly on
factor receptors (FGFR1–4) that contain three Ig-like
receptor scaffolding complexes, or indirectly, via Akt activation and modules, a single transmembrane domain, and a split
GSK3b inhibition. Ras also activates ERK–MAPK downstream signaling. tyrosine-kinase domain. All FGFR isoforms, except for
These pathways jointly lead to LTP expression. Alternatively, NMDAR FGFR4, are involved in a direct interaction with NCAM
can lead to the activation of Rap, for LTD expression. PTEN catalyzes
[49] through its F3 module ectodomain [50,51]. When
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 NCAM mediates cell–cell adhesion (trans-homophilic
the recruitment of endocytic factors and the internalization of AMPARs binding), it clusters into ‘zipper’-like arrays that lead to
for LTD expression. clustering of FGFRs [52]. The resulted increase in the
local concentration of FGFRs triggers a direct receptor–
receptor dimerization, autophosphorylation [53], and acti-
during LTP, whereas MAPK inhibition only produces a vation [54]. This activation results in the recruitment and
partial reduction [35]. stimulation of specific effectors that, in turn, trigger a set
of signaling pathways [55] that can be enhanced by
Rap proteins are small GTPases closely related to Ras. NCAM polysialylation [56] and mediate many of the
They are often related to the control of cellular adhesion functions of NCAM. Among these signaling pathways
and polarity [36], and were originally described to are the FGF receptor substrate 2a (FRS2a), phospho-
antagonize the cell proliferation activity induced by lipase-Cg (PLCg), and Src homologous and collagen A
Ras [37]. Interestingly, in neuronal cells, Ras and Rap (ShcA) that function as links to MAPK and the PI3K
also seem to play antagonistic roles, by modulating LTP pathways [57,58].
and LTD, respectively [38]. The connection between
NMDAR opening and Rap activation during synaptic NCAM/FGFR in synaptic plasticity and
plasticity is more uncertain, but it is likely to involve cognition
synaptically localized Rap regulators, such as SPAR [39] NCAM activity is essential for early synaptogenesis and
or SynGap (which has GAP activity for both Rap and Ras synaptic maturation [46]. In addition, NCAM influences
[40]). Regardless of the specific intermediate steps, it has the strength of excitatory synapses in an activity-depend-
been shown that NMDAR activation does lead to an ent manner [59] and therefore can regulate synaptic
increase in Rap-GTP formation and reduced AMPAR plasticity [60]. The elucidation of the three-dimensional
presence at synapses [41]. In addition, Rap may partici- structure of the extracellular domains of NCAM made it
pate in other forms of AMPAR removal and synaptic possible to design synthetic ligands, which mimic various
depression, such as those mediated by cAMP signaling functions of NCAM. These peptides have contributed
[42,43]. greatly to the elucidation of NCAM’s role in synaptic
functions [61]. The most studied synthetic NCAM-
This antagonistic, but often times overlapping signaling mimetic peptide, termed FGLoop (FGL) was engineered
mediated by Ras and Rap, is itself modulated by the specifically to mimic the functional interaction between
regulation of their effectors. For example, it has been NCAM and FGFR [62]. FGL encompasses the inter-
recently shown that polo-like kinase 2 (Plk2) is able to action domain of NCAM with FGFR: F and G b-strands
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4 Synaptic structure and function
and the interconnecting loop of the second F3 module of of new AMPA receptors into synapses, in response to
NCAM. Similarly to NCAM, FGL was found to elicit NMDAR activation. This is accompanied by enhanced
FGFR-mediated signaling [63] and to induce neuritogen- NMDAR-dependent LTP [66]. Interestingly, these
esis and survival in neuronal cultures [64]. effects are long-lasting. That is, facilitated AMPAR deliv-
ery and enhanced LTP persist at least for two days after
One important advantage of these mimetic peptides is FGL is removed. As for the signaling pathways involved,
that intracellular signaling can be triggered acutely in we observed that FGL triggers an initial PKC activation,
adult animals or brain tissue to assess the role of these which is then followed by persistent CaMKII activation.
pathways in synaptic plasticity, while bypassing their Inhibition of PKC activity during FGL administration
function in neuronal development. Thus, it has been blocks the synaptic and cognitive effects of FGL, whereas
shown that FGL treatment enhances dentate gyrus PI3K and MAPK inhibitors do not [66]. Therefore, it
[65] and CA3-to-CA1 [66] LTP. Importantly, in vivo appears that PKC initiates a cascade of signaling events,
administration of FGL also improved spatial and social which are then translated into a persistent CaMKII
memory retention in rats [62,66,67]. FGL also prevents activity, which is probably responsible for the long-lasting
cognitive impairment induced by stress [68,69] and by synaptic and cognitive effects of FGL. The mechanism(s)
oligomeric b-amyloid [70]. Therefore, FGL acts as an linking FGL-triggered PKC activation to the facilitation
efficient cognitive enhancer, by engaging NCAM-FGFR- of LTP and AMPAR synaptic delivery still remain to be
related signaling. determined. Nevertheless, it seems that only a subset of
the potential signaling events elicited by NCAM-FGFR
As mentioned above, NCAM-FGFR intracellular sig- are dedicated to synaptic plasticity modification
naling may be relayed via PLC, MAPK, and PI3K path- (Figure 2).
ways. Given this complexity, what are the relevant
mediators and synaptic mechanisms for their effect on Conclusions
plasticity and cognition in mature animals? This has also At least with respect to postsynaptic forms of plasticity,
been investigated by means of the FGL peptide. We have there appears to be a straightforward route linking
recently found that FGL acts by facilitating the delivery NMDAR activation to the PIP3 pathway: calcium entry,
activation of Ras-GRF nucleotide exchange factors, for-
Figure 2 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
NCAM FGFR
during LTD. Nevertheless, this scenario is deceivingly
simple (and linear), considering the dense overlap and
feedback mechanisms operating on almost all the
NMDAR AMPAR elements of this route. It is also still unclear how these
Stgz
mechanisms interplay with the ‘canonical’ LTP and
LTD signaling, particularly CaMKII and PP1/PP2B,
PSD95 respectively. This integration will probably require more
Ca2+ direct and incisive approaches to manipulate and image
these pathways acting jointly at postsynaptic terminals.
CaMKII
PI3K PLC As for the synaptic functions of growth factor receptors,
Ras +
Akt PKC particularly NCAM-FGFR signaling, we are still far from
ERK
mTOR MAPK 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-
gene expression
cell remodeling
PKC pathway sensitizes NMDAR-dependent synaptic
potentiation in a long-lasting manner, by facilitating
Current Opinion in Neurobiology
the synaptic delivery of AMPARs. From a mechanistic
point of view, there are several missing pieces of infor-
Facilitation of AMPAR synaptic delivery by NCAM-FGFR signaling.
Heterophilic interactions between the extracellular immunoglobulin (Ig)- mation, particularly, the direct targets of PKC mediating
like domains of NCAM with FGFR lead to the activation of three major this effect. As described here, this pathway would not be
signaling axes: ERK–MAPK, PI3K-AKT-mTOR, and PLC-PKC. The two an integral part of the synaptic plasticity process, but
former ones are critical for changes in gene expression leading to cell rather a modulator of its efficacy. Obviously, this obser-
remodeling, and are involved in several forms of synaptic plasticity. The
PKC pathway is uniquely required for the facilitation of the synaptic
vation does not detract from its relevance. In fact, the
delivery of AMPARs during NMDAR-dependent LTP. This process is molecular dissection of these intertwined signaling path-
accompanied by a long-lasting activation of CaMKII. ways is of the outmost importance, considering that most
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