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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 ( and ´Esteban, Jose A ( 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 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 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 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 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
  5. 5. CONEUR-1047; NO. OF PAGES 7 Common pathways for growth and for plasticity Knafo and Esteban 5physiological (and pathological) variations in cognitive 18. Wang Y, Cheng A, Mattson MP: The PTEN phosphatase is essential for long-term depression of hippocampal synapses.function are likely due to modulatory influences on ‘core’ Neuromol Med 2006, 8:329-336.synaptic plasticity mechanisms. 19. Di Paolo G, De Camilli P: Phosphoinositides in cell regulation and membrane dynamics. Nature 2006, 443:651-657.References and recommended reading 20. Gong LW, De Camilli P: Regulation of postsynaptic AMPAPapers of particular interest, published within the period of review, responses by synaptojanin 1. Proc Natl Acad Sci U S A 2008,have been highlighted as: 105:17561-17566. of special interest 21. Unoki T, Matsuda S, Kakegawa W, Van NT, Kohda K, Suzuki A, of outstanding interest Funakoshi Y, Hasegawa H, Yuzaki M, Kanaho Y: NMDA receptor- mediated PIP5K activation to produce PI(4,5)P(2) is essential for AMPA receptor endocytosis during LTD. Neuron 2012,1. Frank CL, Tsai LH: Alternative functions of core cell cycle 73:135-148. regulators in neuronal migration, neuronal maturation, and Using a gene knockdown approach, the authors demonstrate that PIP2 synaptic plasticity. Neuron 2009, 62:312-326. formation is regulated in response to NMDAR activation, and this process is critical for the internalization of AMPARs during LTD.2. Yoshii A, Constantine-Paton M: Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev 22. Horne EA, Dell’Acqua ML: Phospholipase C is required for Neurobiol 2010, 70:304-322. changes in postsynaptic structure and function associated with NMDA receptor-dependent long-term depression. J3. Thomas GM, Huganir RL: MAPK cascade signalling and Neurosci 2007, 27:3523-3534. synaptic plasticity. Nat Rev Neurosci 2004, 5:173-183. 23. Kim JI, Lee HR, Sim SE, Baek J, Yu NK, Choi JH, Ko HG, Lee YS,4. Sweatt JD: Mitogen-activated protein kinases in synaptic Park SW, Kwak C et al.: PI3Kgamma is required for NMDA plasticity and memory. Curr Opin Neurobiol 2004, 14:311-317. receptor-dependent long-term depression and behavioral5. Ye X, Carew TJ: Small G protein signaling in neuronal plasticity flexibility. Nat Neurosci 2011, 14:1447-1454. and memory formation: the specific role of ras family proteins. Using a new mouse knockout model, the authors identify a specific PIP3 Neuron 2010, 68:340-361. synthesizing enzyme (PI3Kgamma) as required for LTD and specific cognitive functions.6. Cantley LC: The phosphoinositide 3-kinase pathway. Science 2002, 296:1655-1657. 24. Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS, Backos DS, Carvalho AL, Esteban JA, Duarte CB: Brain-derived7. Wymann MP, Pirola L: Structure and function of neurotrophic factor regulates the expression and synaptic phosphoinositide 3-kinases. Biochim Biophys Acta 1998, delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole 1436:127-150. propionic acid receptor subunits in hippocampal neurons. J Biol Chem 2007, 282:12619-12628.8. Maehama T, Dixon JE: PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 25. Li X, Wolf ME: Brain-derived neurotrophic factor rapidly 1999, 9:125-128. increases AMPA receptor surface expression in rat nucleus accumbens. Eur J Neurosci 2011, 34:190-198.9. Reichardt LF: Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B: Biol Sci 2006, 361:1545-1564. 26. Frey U, Krug M, Reymann KG, Matthies H: Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP10. Ma XM, Blenis J: Molecular mechanisms of mTOR-mediated phenomena in the hippocampal CA1 region in vitro. Brain Res translational control. Nat Rev Mol Cell Biol 2009, 10:307-318. 1988, 452:57-65.11. 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 is 27. Harvey CD, Yasuda R, Zhong H, Svoboda K: The spread of Ras required for AMPA receptor insertion during LTP of mEPSCs in activity triggered by activation of a single dendritic spine. cultured hippocampal neurons. Neuron 2003, 38:611-624. Science 2008, 321:136-140. In this work, using multiphoton fluorescence microscopy and focal12. Arendt KL, Royo M, Fernandez-Monreal M, Knafo S, Petrok CN, synaptic stimulation, the authors determine the temporal and spatial Martens JR, Esteban JA: PIP3 controls synaptic function by details of Ras activation upon NMDAR opening during LTP. maintaining AMPA receptor clustering at the postsynaptic membrane. Nat Neurosci 2010, 13:36-44. 28. Feig LA: Regulation of neuronal function by Ras-GRFUsing electrophysiological and imaging techniques, the authors describe exchange factors. Genes Cancer 2011, 2:306-319.specific functions of PIP3 at the postsynaptic terminal, which involve the 29. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R,maintenance of AMPARs at the synaptic membrane. Pellegrino C, Ben-Ari Y, Clapham DE, Medina I: The NMDA13. Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, receptor is coupled to the ERK pathway by a direct interaction Wu D, Saule E, Bouschet T et al.: LTP inhibits LTD in the between NR2B and RasGRF1. Neuron 2003, 40:775-784. hippocampus via regulation of GSK3beta. Neuron 2007, 53:703-717. 30. Li S, Tian X, Hartley DM, Feig LA: Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the14. Zimmermann P: The prevalence and significance of PDZ induction of long-term potentiation and long-term depression. domain–phosphoinositide interactions. Biochim Biophys Acta J Neurosci 2006, 26:1721-1729. 2006, 1761:947-956. 31. Shilyansky C, Lee YS, Silva AJ: Molecular and cellular15. Yoshii A, Constantine-Paton M: BDNF induces transport of PSD- mechanisms of learning disabilities: a focus on NF1. Annu Rev 95 to dendrites through PI3K-AKT signaling after NMDA Neurosci 2010, 33:221-243. receptor activation. Nat Neurosci 2007, 10:702-711. 32. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y,16. Yin HL, Janmey PA: Phosphoinositide regulation of the actin Pellerin S, Dobrzeniecka S, Cote M, Perreau-Linck E, Carmant L cytoskeleton. Annu Rev Physiol 2003, 65:761-789. et al.: Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med 2009, 360:599-605.17. Jurado S, Benoist M, Lario A, Knafo S, Petrok CN, Esteban JA: PTEN is recruited to the postsynaptic terminal for NMDA 33. Castellano E, Downward J: RAS interaction with PI3K: more receptor-dependent long-term depression. EMBO J 2010, than just another effector pathway. Genes Cancer 2011, 2:261- 29:2827-2840. 274.PTEN is a major regulator of cellular and organ growth during develop-ment. In this work the authors dissect distinct functions of PTEN on 34. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V,mature synapses, particularly as a mediator of long-term depression van Aelst L, Zhu JJ: State-dependent Ras signaling and AMPA(LTD). receptor trafficking. Genes Dev 2005, 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
  6. 6. CONEUR-1047; NO. OF PAGES 76 Synaptic structure and function35. Patterson MA, Szatmari EM, Yasuda R: AMPA receptors are 53. Mohammadi M, Olsen SK, Ibrahimi OA: Structural basis for exocytosed in stimulated spines and adjacent dendrites in a fibroblast growth factor receptor activation. Cytokine Growth Ras-ERK-dependent manner during long-term potentiation. Factor Rev 2005, 16:107-137. Proc Natl Acad Sci U S A 2010, 107:15951-15956. 54. Kochoyan A, Poulsen FM, Berezin V, Bock E, Kiselyov VV:36. Bos JL: Linking Rap to cell adhesion. Curr Opin Cell Biol 2005, Structural basis for the activation of FGFR by NCAM. Protein 17:123-128. Sci 2008, 10:1698-1705.37. Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M: A ras- 55. Beenken A, Mohammadi M: The FGF family: biology, related gene with transformation suppressor activity. Cell pathophysiology and therapy. Nat Rev Drug Discov 2009, 8:235- 1989, 56:77-84. 253.38. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R: Ras and Rap 56. Li J, Dai G, Cheng YB, Qi X, Geng MY: Polysialylation promotes control AMPA receptor trafficking during synaptic plasticity. neural cell adhesion molecule-mediated cell migration in a Cell 2002, 110:443-455. fibroblast growth factor receptor-dependent manner, but independent of adhesion capability. Glycobiology 2011,39. Pak DT, Yang S, Rudolph-Correia S, Kim E, Sheng M: Regulation 21:1010-1018. of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 2001, 31:289-303. 57. Eswarakumar VP, Lax I, Schlessinger J: Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev40. Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE: 2005, 16:139-149. SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent 58. Dailey L, Ambrosetti D, Mansukhani A, Basilico C: Mechanisms synaptic AMPA receptor potentiation. Neuron 2004, underlying differential responses to FGF signaling. Cytokine 43:563-574. Growth Factor Rev 2005, 16:233-247.41. Xie Z, Huganir RL, Penzes P: Activity-dependent dendritic spine 59. Dityatev A, Dityateva G, Schachner M: Synaptic strength as a structural plasticity is regulated by small GTPase Rap1 and its function of post-versus presynaptic expression of the target AF-6. Neuron 2005, 48:605-618. neural cell adhesion molecule NCAM. Neuron 2000, 26:207-217.42. Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME, Xie Z, Jones KA, Quilliam LA, Prakriya M 60. Muller D, Wang C, Skibo G, Toni N, Cremer H, Calaora V, et al.: Epac2 induces synapse remodeling and depression and Rougon G, Kiss JZ: PSA NCAM is required for activity-induced its disease-associated forms alter spines. Nat Neurosci 2009, synaptic plasticity. Neuron 1996, 17:413-422. 12:1275-1284.This study provides an upstream activator and a downstream mechan- 61. Berezin V, Bock E: NCAM mimetic peptides: pharmacologicalistic link for the role of Rap in synaptic depression and spine remodel- and therapeutic potential. J Mol Neurosci 2004,ing. 22:33-39.43. Ster J, de Bock F, Bertaso F, Abitbol K, Daniel H, Bockaert J, 62. Cambon K, Hansen SM, Venero C, Herrero AI, Skibo G, Berezin V, Fagni L: Epac mediates PACAP-dependent long-term Bock E, Sandi C: A synthetic neural cell adhesion molecule depression in the hippocampus. J Physiol 2009, mimetic peptide promotes synaptogenesis, enhances 587:101-113. presynaptic function, and facilitates memory consolidation. J Neurosci 2004, 24:4197-4204.44. Lee KJ, Lee Y, Rozeboom A, Lee JY, Udagawa N, Hoe HS, Pak DT: 63. Chen Y, Li S, Berezin V, Bock E: The fibroblast growth factor Requirement for Plk2 in orchestrated ras and rap signaling, receptor (FGFR) agonist FGF1 and the neural cell adhesion homeostatic structural plasticity, and memory. Neuron 2011, molecule-derived peptide FGL activate FGFR substrate 69:957-973. 2alpha differently. J Neurosci Res 2010, 88:1882-1889.This work illustrates how Ras and Rap is integrated at synaptic terminals,by means of a specific kinase that phosphorylates multiple Ras and Rap 64. Neiiendam JL, Kohler LB, Christensen C, Li S, Pedersen MV,regulators. Ditlevsen DK, Kornum MK, Kiselyov VV, Berezin V, Bock E: An NCAM-derived FGF-receptor agonist, the FGL-peptide,45. Kennedy MB, Beale HC, Carlisle HJ, Washburn LR: Integration of induces neurite outgrowth and neuronal survival in primary rat biochemical signalling in spines. Nat Rev Neurosci 2005, 6:423- neurons. J Neurochem 2004, 91:920-935. 434. ´ 65. Dallerac G, Zerwas M, Novikova T, Callu D, Leblanc-Veyrac P,46. Washbourne P, Dityatev A, Scheiffele P, Biederer T, Weiner JA, ´ Bock E, Berezin V, Rampon C, Doyere V: The neural cell Christopherson KS, El-Husseini A: Cell adhesion molecules in adhesion molecule-derived peptide FGL facilitates long-term synapse formation. J Neurosci 2004, 24:9244-9249. plasticity in the dentate gyrus in vivo. Learn Mem 2011, 18:306-47. Skaper SD, Moore SE, Walsh FS: Cell signalling cascades 313. regulating neuronal growth-promoting and inhibitory cues. Using electrophysiological techniques in awake, freely moving animals, Prog Neurobiol 2001, 65:593-608. the authors determine that the NCAM-mimetic peptide FGL produces a long-lasting enhancement of synaptic plasticity.48. Maness PF, Schachner M: Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon 66. Knafo S, Venero C, Sanchez-Puelles C, Pereda-Perez I, Franco A, guidance and neuronal migration. Nat Neurosci 2007, Sandi C, Suarez LM, Solis JM, Alonso-Nanclares L, Martin ED 10:19-26. et al.: Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement. PLoS Biol49. Christensen C, Berezin V, Bock E: Neural cell adhesion molecule 2012, 2 doi: 10.1371/journal.pbio.1001262. differentially interacts with isoforms of the fibroblast growth Using a combination of electrophysiological, imaging, and behavioral factor receptor. Neuroreport 2011, 22:727-732. techniques, the authors dissect the signaling pathways and synaptic mechanisms by which FGL enhances cognitive performance in spatial50. Hansen SM, Li S, Bock E, Berezin V: Synthetic NCAM-derived learning and memory tasks. ligands of the fibroblast growth factor receptor. Adv Exp Med Biol 2010, 663:355-372. 67. Secher T, Novitskaia V, Berezin V, Bock E, Glenthoj B, Klementiev B: A neural cell adhesion molecule-derived51. Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N, fibroblast growth factor receptor agonist, the FGL-peptide, Soroka V, Pedersen N, Tsetlin V, Poulsen FM, Berezin V et al.: promotes early postnatal sensorimotor development and Structural basis for a direct interaction between FGFR1 and enhances social memory retention. Neuroscience 2006, NCAM and evidence for a regulatory role of ATP. Structure 141:1289-1299. 2003, 11:691-701. 68. Borcel E, Perez-Alvarez L, Herrero AI, Brionne T, Varea E,52. Kiselyov VV, Soroka V, Berezin V, Bock E: Structural biology of Berezin V, Bock E, Sandi C, Venero C: Chronic stress in NCAM homophilic binding and activation of FGFR. J adulthood followed by intermittent stress impairs spatial Neurochem 2005, 94:1169-1179. memory and the survival of newborn hippocampal cells inCurrent 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
  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, 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