Knafo and esteban con

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Knafo and esteban con

  1. 1. CONEUR-1047; NO. OF PAGES 7 Available online at www.sciencedirect.comCommon pathways for growth and for plasticity ´Shira Knafo and Jose A EstebanCell growth and differentiation in developing tissues are, at first remains as to how signaling pathways instructing growthimpression, quite different endeavors from readjusting synaptic and differentiation switch their output to drive changes instrength during activity-dependent synaptic plasticity in mature synaptic strength during plasticity. Are these pathwaysneurons. Nevertheless, it is becoming increasingly clear that essentially wired in the same manner, just producingthese 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 downstreamdivision (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 doessynaptic plasticity) is only starting to be elucidated. Here we the induction of activity-dependent synaptic plasticityreview the latest findings on two prototypical examples of these converge into similar pathways as those initiated byshared mechanisms: the Ras-PI3K pathway and the extrinsic growth and survival signals? To address theseintracellular signaling elicited by neural cell adhesion molecules questions, we will consider two examples from recentinteracting with growth factor receptors. literature: the signaling pathways driven by phosphoino- sitide-3,4,5-trisphosphate (PIP3) and by neuronal cellAddress adhesion molecule-fibroblast growth factor receptor ´ ´Centro de Biologıa Molecular ‘‘Severo Ochoa’’ (CSIC-UAM), Nicolas (NCAM-FGFR), and their role in plasticity mechanismsCabrera 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 tyrosineIntroduction kinases, which upon activation and transphosphorylationThere 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, withdifferentiation programs in early development, and those the concomitant synthesis of PIP3, is then typicallymediating 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-mTORand 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 strengththe 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 areFor example, at a basic cell biology level, the same type of required for the delivery of new AMPARs into synapses inmembrane 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 theor for a migrating cell to add patches of plasma membrane synaptic membrane [12]. However, it has been veryin specific directions. Nevertheless, the question still challenging to identify downstream effectors of thesewww.sciencedirect.com Current Opinion in Neurobiology 2012, 22:1–7 Please cite this article in press as: Knafo S, Esteban JA. Common pathways for growth and for plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008
  2. 2. CONEUR-1047; NO. OF PAGES 72 Synaptic structure and functionsignaling molecules that directly connect with the regu- systems) impairs NMDAR-dependent LTD withoutlation of synaptic strength. On the one hand, canonical altering LTP or mGluR-dependent LTD [23].downstream signaling from PIP3 is likely involved, sinceAkt activation and GSK3b inhibition are required forefficient LTP expression [13]. On the other hand, direct Upstream regulators. The antagonism of Raseffects of PIP3 on the synaptic scaffold cannot be and Rap signalingexcluded, since multiple PDZ domains have phosphoi- What would be the initiating events for the engagementnositide binding capabilities [14]. Indeed, PIP3 depletion of PI3K and PTEN in synaptic plasticity? As mentionedreduces the accumulation of PSD-95 at spines [12], and earlier, neurotrophins and related growth factors arePI3K 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 abundantAdditionally, PIP3 regulates the activity of multiple Rac literature on the effects of BDNF on synaptic plasticityand Rho effectors [16]. In this manner, it may play and cognition in adult animals [2]. In fact, BDNF canimportant (and complex) functions in the remodeling trigger AMPAR synthesis and delivery into synapses inof the actin cytoskeleton during synaptic plasticity. differentiated neurons [24,25]. Nevertheless, we may expect that neurotrophin-independent mechanisms areAnalogous to the connection between PIP3 formation and also at play, particularly for early phases of synapticsynaptic potentiation, PIP3 turnover by the lipid phos- plasticity (E-LTP, E-LTD), which do not require newphatase PTEN has been linked to synaptic depression protein synthesis [26].[17,18]. Thus, PTEN is recruited to the postsynapticcomplex in a PDZ-dependent manner in response to Some of the most paradigmatic forms of postsynapticNMDAR 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 thatent long-term depression (LTD), but not for other forms NMDARs will be able to trigger the PIP3 pathway inof synaptic plasticity, such as metabotropic glutamate these forms of plasticity. Indeed, the connection betweenreceptor (mGluR)-dependent LTD or LTP [17]. NMDARs and PIP3 can be established by piecingSimilar 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–Rapthis 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 theIt is important to keep in mind that PTEN’s action may experimental evidence summarized as follows. Calciumrely on the local depletion of PIP3, with the subsequent entry via NMDARs is able to produce local and transientremoval of synaptic AMPARs [12], but also on the local activation of Ras at spines [27], possibly mediated byproduction of PIP2 upon dephosphorylation of PIP3. PIP2 calcium-dependent Ras activators, such as the guanineis a recruitment factor for multiple endocytic proteins, nucleotide exchange factors Ras-GRF1 and 2, which aresuch 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], andthe PIP2 synthesizing enzyme PIP5Kg661, associates genetic deletions of Ras-GRF1 or 2 differentially alterwith the endocytic machinery at postsynaptic sites in NMDAR-dependent synaptic plasticity [30]. Negativeresponse 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] andsubstrate for further enzymatic turnover by phospholipase SynGap [32] are associated to cognitive dysfunction inC [22]. These observations underscore the complexities humans.of phosphoinositide metabolism, where turnover of onephosphoinositide species will generate potential sub- Ras is a central signaling hub for the activation of manystrates for further downstream signaling. PI3K isoforms [33]. Interestingly, Ras may differentially activate PI3K or mitogen-activated protein kinaseIt is also important to avoid the oversimplification that (MAPK), potentially providing further specificity (andPIP2 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 bothare 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]. Inreported that genetic deletion of PI3Kg (which is specifi- agreement with this interpretation, a dominant negativecally expressed in the brain, immune and cardiovascular form of Ras strongly blocks AMPAR surface deliveryCurrent Opinion in Neurobiology 2012, 22:1–7 www.sciencedirect.com Please cite this article in press as: Knafo S, Esteban JA. Common pathways for growth and for plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008
  3. 3. CONEUR-1047; NO. OF PAGES 7 Common pathways for growth and for plasticity Knafo and Esteban 3Figure 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 heterophilicSimplified 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 thesensitive Ras-GRFs nucleotide exchange factors lead to the formation of heterophilic partners of NCAM are the fibroblast growthactive Ras, with the concomitant activation of PI3K. This enzymecatalyzes the formation of PIP3, which in turn may act directly on factor receptors (FGFR1–4) that contain three Ig-likereceptor scaffolding complexes, or indirectly, via Akt activation and modules, a single transmembrane domain, and a splitGSK3b inhibition. Ras also activates ERK–MAPK downstream signaling. tyrosine-kinase domain. All FGFR isoforms, except forThese pathways jointly lead to LTP expression. Alternatively, NMDAR FGFR4, are involved in a direct interaction with NCAMcan lead to the activation of Rap, for LTD expression. PTEN catalyzes [49] through its F3 module ectodomain [50,51]. Whenthe turnover of PIP3 to form PIP2. Inhibition of Akt and activation ofGSK3b will favor LTD induction. In addition, formation of PIP2 will lead to NCAM mediates cell–cell adhesion (trans-homophilicthe recruitment of endocytic factors and the internalization of AMPARs binding), it clusters into ‘zipper’-like arrays that lead tofor 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 andpartial reduction [35]. stimulation of specific effectors that, in turn, trigger a set of signaling pathways [55] that can be enhanced byRap proteins are small GTPases closely related to Ras. NCAM polysialylation [56] and mediate many of theThey are often related to the control of cellular adhesion functions of NCAM. Among these signaling pathwaysand 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 ARas [37]. Interestingly, in neuronal cells, Ras and Rap (ShcA) that function as links to MAPK and the PI3Kalso seem to play antagonistic roles, by modulating LTP pathways [57,58].and LTD, respectively [38]. The connection betweenNMDAR opening and Rap activation during synaptic NCAM/FGFR in synaptic plasticity andplasticity is more uncertain, but it is likely to involve cognitionsynaptically localized Rap regulators, such as SPAR [39] NCAM activity is essential for early synaptogenesis andor 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 synapticincrease in Rap-GTP formation and reduced AMPAR plasticity [60]. The elucidation of the three-dimensionalpresence at synapses [41]. In addition, Rap may partici- structure of the extracellular domains of NCAM made itpate in other forms of AMPAR removal and synaptic possible to design synthetic ligands, which mimic variousdepression, 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 engineeredmediated by Ras and Rap, is itself modulated by the specifically to mimic the functional interaction betweenregulation 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-strandswww.sciencedirect.com Current Opinion in Neurobiology 2012, 22:1–7 Please cite this article in press as: Knafo S, Esteban JA. Common pathways for growth and for plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008
  4. 4. CONEUR-1047; NO. OF PAGES 74 Synaptic structure and functionand the interconnecting loop of the second F3 module of of new AMPA receptors into synapses, in response toNCAM. Similarly to NCAM, FGL was found to elicit NMDAR activation. This is accompanied by enhancedFGFR-mediated signaling [63] and to induce neuritogen- NMDAR-dependent LTP [66]. Interestingly, theseesis 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 afterOne 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 administrationfunction in neuronal development. Thus, it has been blocks the synaptic and cognitive effects of FGL, whereasshown 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 CaMKIImemory retention in rats [62,66,67]. FGL also prevents activity, which is probably responsible for the long-lastingcognitive 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 facilitationefficient cognitive enhancer, by engaging NCAM-FGFR- of LTP and AMPAR synaptic delivery still remain to berelated signaling. determined. Nevertheless, it seems that only a subset of the potential signaling events elicited by NCAM-FGFRAs mentioned above, NCAM-FGFR intracellular sig- are dedicated to synaptic plasticity modificationnaling may be relayed via PLC, MAPK, and PI3K path- (Figure 2).ways. Given this complexity, what are the relevantmediators and synaptic mechanisms for their effect on Conclusionsplasticity 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 linkingrecently 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 mediatinglike domains of NCAM with FGFR lead to the activation of three major this effect. As described here, this pathway would not besignaling axes: ERK–MAPK, PI3K-AKT-mTOR, and PLC-PKC. The two an integral part of the synaptic plasticity process, butformer 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. ThePKC pathway is uniquely required for the facilitation of the synaptic vation does not detract from its relevance. In fact, thedelivery 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 mostCurrent Opinion in Neurobiology 2012, 22:1–7 www.sciencedirect.com Please cite this article in press as: Knafo S, Esteban JA. Common pathways for growth and for plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008
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Common pathways for growth and for plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008
  7. 7. CONEUR-1047; NO. OF PAGES 7 Common pathways for growth and for plasticity Knafo and Esteban 7 aging animals: prevention by FGL, a peptide mimetic of neural 70. Klementiev B, Novikova T, Novitskaya V, Walmod PS, cell adhesion molecule. Behav Pharmacol 2008, 19:41-49. Dmytriyeva O, Pakkenberg B, Berezin V, Bock E: A neural cell adhesion molecule-derived peptide reduces69. Bisaz R, Schachner M, Sandi C: Causal evidence for the neuropathological signs and cognitive impairment induced by involvement of the neural cell adhesion molecule. NCAM, in Abeta25-35. Neuroscience 2007, 145:209-224. chronic stress-induced cognitive impairments. Hippocampus 2011, 21:56-71.www.sciencedirect.com Current Opinion in Neurobiology 2012, 22:1–7 Please cite this article in press as: Knafo S, Esteban JA. Common pathways for growth and for plasticity, Curr Opin Neurobiol (2012), doi:10.1016/j.conb.2012.02.008

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