Regulation of local translation at the synapse by BDNF

Progress in Neurobiology 92 (2010) 505–516

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Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

Regulation of local translation at the synapse by BDNF Ana Rita Santos, Diogo Comprido, Carlos B. Duarte * Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Largo Marqueˆs de Pombal, 3004-517 Coimbra, Portugal

A R T I C L E I N F O

A B S T R A C T

Article history: Received 18 May 2010 Received in revised form 29 July 2010 Accepted 9 August 2010

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in synaptic plasticity, in part due to changes in local protein synthesis. Activation of TrkB (tropomyosin-related kinase B) receptors for BDNF triggers several parallel signaling pathways, including the Ras/ERK, the phosphatidylinositol 3kinase (PI3-K) and the phospholipase C-g pathways. Recent studies have elucidated some of the signaling mechanisms that contribute to the regulation of translation activity by BDNF, through modulation of initiation and elongation phases, but the resulting changes in the proteome are not yet fully characterized. The proteins synthesized in response to activation of TrkB receptors by BDNF depend on the mRNAs that are available locally, after delivery and transport along dendrites. Recent studies have shown that BDNF may also play a regulatory role at this level. Furthermore, BDNF regulates transcription activity, thereby affecting the array of mRNAs available to be transported along dendrites. This review highlights the recent advances in the understanding of the diversity of mechanisms that contribute to the regulation of the synaptic proteome by BDNF, which may account for its role in synaptic plasticity. ß 2010 Elsevier Ltd. All rights reserved.

Keywords: BDNF Local translation Synaptic regulation mRNA trafficking RNA targeting RNA granules RNA-binding proteins

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Local protein synthesis in dendrites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BDNF and synaptic plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. BDNF release and synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. BDNF and synaptic plasticity in the hippocampus . . . . . . . . . . . . . . 2.3. TrkB receptors and synaptic plasticity in other brain regions . . . . . Transcription- and translation-independent synaptic regulation by BDNF . Regulation of the translation machinery by BDNF . . . . . . . . . . . . . . . . . . . . Dendritic transcripts regulated by BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Dendritic transcripts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. BDNF and local translation at the synapse . . . . . . . . . . . . . . . . . . . . 5.3. Effects of BDNF on post-transcriptional modulators . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Local protein synthesis in dendrites Abbreviations: 4EBPs, eIF4E-binding proteins; BC1, brain cytoplasmic RNA; BDNF, brain-derived neurotrophic factor; CREB, cAMP-response element binding protein; CYFIP1/Sra1, cytoplasmic FMR1 interacting protein 1; eEF, eukaryotic elongation factor; eIF, eukaryotic initiation factor; ERK, extracellular signal-regulated protein kinase; FMRP, fragile X mental retardation protein; FXS, Fragile X Syndrome; Limk1, Lim-domain containing kinase 1; LTP, long-term potentiation; Mef2, myocyte enhancing factor 2; miRNA, micro RNA; mTOR, mammalian target of rapamycin; NAc, nucleus accumbens; PI3-K, phosphatidylinositol 3-kinase; Pum2, Pumilio2; RISC, RNA-induced silencing complex; RNP, ribonucleoproteins; TrkB, tropomyosin-related kinase B; VTA, ventral tegmental area. * Corresponding author. Tel.: +351 239104397; fax: +351 239822776. E-mail address: [email protected] (C.B. Duarte). 0301-0082/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2010.08.004

Although the bulk of mRNAs are translated in the neuronal cell body, local translation of specific mRNAs might be of particular importance for the regulation of protein expression within dendrites and growing axons. The hypothesis that protein translation can take place in post-synaptic compartments came from the pioneer study by Steward and Levy (1982) who observed polyribosomes at the base of several spines in a rosette-like structure, which is the distinctive evidence that they are bound to mRNAs and actively engaged in protein synthesis. The hypothesis

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of local translation suggests that several key components can be specifically synthesized and regulated by signaling events initiated in a specific synapse. Since then many studies have addressed this issue, and it is now clear that local protein synthesis at synaptic sites occurs independently of the soma, and various stimuli are known to induce local protein synthesis in dendrites. Several neural processes have been related to local protein synthesis, such as synaptic plasticity [reviewed in (Costa-Mattioli et al., 2009; Steward and Schuman, 2001)], neurite growth and development (Sebeo et al., 2009). The number of identified mRNAs that are localized to the synapse is increasing, many of them encoding synaptic proteins, including most components of the post-synaptic density, and components of the translation machinery (Eberwine et al., 2002; Kye et al., 2007; Poon et al., 2006; Zhong et al., 2006). Studies have been performed to clarify how local translation is regulated by extracellular signals, including neurotransmitters and trophic factors, but the mechanisms that target specific mRNAs to dendrites and their selective docking at specific synapses remain largely unknown. Factors controlling local translation activity and those affecting the transport of mRNA to subcellular sites regulate the specificity of translation. The neurotrophin BDNF plays an important role in synaptic regulation in the hippocampus, acting in part by a translationdependent mechanism. Although the synaptic effects of BDNF have been extensively characterized, the mechanisms underlying BDNFinduced local changes in the synaptic proteome and their role in synaptic plasticity are not fully understood. In the present review we highlight recent advances in the understanding of BDNFmediated regulation of local translation in dendrites which may contribute to long-term changes in synaptic activity. 2. BDNF and synaptic plasticity Changes in synaptic connectivity due to alterations in activity and/or following structural modifications are thought to underlie learning and memory formation. The long-term potentiation (LTP) of hippocampal synapses is the most studied form of synaptic plasticity, and comprises three sequential phases: short-term potentiation, early-LTP (E-LTP) and late LTP (L-LTP). The first two phases are transcription and translation independent, lasting for 1–2 h, and the latter phase depends on transcription and de novo protein synthesis, lasting for hours to days [reviewed in (CostaMattioli et al., 2009; Malenka and Bear, 2004)]. The role of BDNF in synaptic plasticity, as well as in acquisition, consolidation, and retention of hippocampal-dependent memory has been reviewed elsewhere (Bramham and Messaoudi, 2005; Cowansage et al., 2010; Lu et al., 2008; Minichiello, 2009) and is beyond the scope of this article. In this section we will mainly focus on the most relevant evidences showing a role for the neurotrophin in LTP in the hippocampus. 2.1. BDNF release and synaptic plasticity Different protocols of electrical stimulation leading to LTP at glutamatergic synapses have been shown to induce the release of BDNF, although the relative contribution of axons and dendrites to the release of the endogenous neurotrophin is still not fully elucidated [(Aicardi et al., 2004; Gartner and Staiger, 2002; Hartmann et al., 2001; Nagappan et al., 2009); for recent reviews see also (Kuczewski et al., 2009; Lessmann and Brigadski, 2009)]. It was suggested that secretion of BDNF from the pre-synaptic terminal may contribute to E-LTP through modification of existing pre- and post-synaptic proteins (Caldeira et al., 2007a; Gartner et al., 2006; Jovanovic et al., 2000; Minichiello et al., 1999; PozzoMiller et al., 1999; Xu et al., 2000; Zakharenko et al., 2003). In contrast, long-term maintenance of L-LTP would rely on the

continuous supply of BDNF through the activity-dependent transcription and translation in the post-synaptic neurons (Lu et al., 2008), and subsequent stimulation of de novo protein synthesis crucial for the maintenance of L-LTP [see below; (Kang and Schuman, 1996; Schratt et al., 2004; Yin et al., 2002)]. BDNF is released mainly by a Ca2+-dependent mechanism, and studies performed in cultured neurons showed that voltage-gated Ca2+ channels, NMDA receptors and intracellular stores contribute to the exocytosis of BDNF-containing vesicles [e.g. (Hartmann et al., 2001; Kolarow et al., 2007)]. It is thought that the mature form of BDNF (mBDNF) plays a key role in LTP through activation of TrkB receptors, whereas the precursor form of the neurotrophin (proBDNF) induces long-term depression through binding to a different class of receptors, the p75NTR (Woo et al., 2005). In cultured hippocampal neurons the ratio proBDNF/mBDNF accumulated extracellularly depends on the frequency of electrical stimulation. High-frequency stimulation induces the secretion of proteases that cleave proBDNF, leading to the extracellular accumulation of mBDNF (Nagappan et al., 2009). Accordingly, the cleavage of proBDNF by tPA/plasmin plays an important role in LTP in the hippocampus (Pang et al., 2004). However, others have suggested that hippocampal neurons store and release mainly BDNF in its mature form (Matsumoto et al., 2008; Nomoto et al., 2007), and a role for mBDNF recycling in the maintenance of LTP was also proposed (Santi et al., 2006). 2.2. BDNF and synaptic plasticity in the hippocampus Activation of TrkB receptors by BDNF has been shown to play a role in LTP in different hippocampal synapses. Thus, LTP in the hippocampus CA1 region is attenuated when endogenous BDNF is sequestered with the TrkB-immunoglobulin G fusion protein and similar results were obtained in the presence of BDNF- or TrkBantiserum (Chen et al., 1999; Figurov et al., 1996; Kang et al., 1997; Korte et al., 1998; Rex et al., 2007). TrkB- or BDNF-deficient mice also show an impairment of LTP (Korte et al., 1995, 1996; Minichiello et al., 1999; Pozzo-Miller et al., 1999; Xu et al., 2000), and the effects in the latter condition can be rescued by acute application of BDNF or by virus-mediated application of the neurotrophin (Figurov et al., 1996; Korte et al., 1996a; Patterson et al., 1996). Interestingly, blocking of BDNF with antibodies impaired LTP induced by theta-burst stimulation or by pairing post-synaptic depolarization and low frequency stimulation, but not by tetanic stimulation, whereas in BDNF deficient mice LTP induced by tetanic stimulation is also significantly impaired (Chen et al., 1999; Figurov et al., 1996; Kang et al., 1997; Korte et al., 1995, 1996; Patterson et al., 1996; Rex et al., 2007). This discrepancy was attributed to an excessive release of BDNF upon tetanic stimulation, which may exceed the buffering capacity of the antibodies used, and/or to the activation of distinct signaling pathways necessary for LTP induction (Chen et al., 1999). BDNF also has a facilitatory effect in the induction of LTP under conditions of synaptic stimulation that would not normally induce synaptic potentiation in the hippocampal CA1 region (Figurov et al., 1996; Kovalchuk et al., 2002). Furthermore, acute application of BDNF to hippocampal slices induces synaptic potentiation in the hippocampal CA1 region by a mechanism dependent on protein synthesis (Ji et al., 2010; Kang and Schuman, 1995, 1996). Similar results were obtained in the dentate gyrus following in vivo intrahippocampal infusion of the neurotrophin (Messaoudi et al., 1998), and these effects of BDNF were shown to be dependent of transcription and translation (Messaoudi et al., 2002; Ying et al., 2002). In agreement with the role of BDNF in synaptic plasticity, several lines of evidence suggest that the BDNF–TrkB system plays a role in memory acquisition and consolidation [reviewed in (Lu et al., 2008)].

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The TrkB receptors for BDNF belong to the tyrosine kinase family of receptor proteins and activate multiple signaling responses, including the Ras/ERK (extracellular signal-regulated protein kinase) pathway, the PI3-K (phosphatidylinositol 3-kinase) pathway and phospholipase C-g (Carvalho et al., 2008). The signaling mechanisms that operate downstream of the TrkB receptors in LTP were investigated using mice with targeted mutations in either the Shc- or the PLCg-binding sites of TrkB (Minichiello et al., 2002). These studies showed that the early and late phases of LTP in the CA1 region of the hippocampus are dependent on the TrkB coupling to PLCg, whereas mutation of the Shc docking site on TrkB was without effect on LTP. Selective preand post-synaptic expression of the PLCg pleckstrin homology domain with viral vectors, which blocks PLCg signalling and Ins(1,4,5)P3 production, abrogated the effect of TrkB receptors on LTP. However, selective blockade of pre- or post-synaptic signaling alone did not result in a significant reduction of LTP, showing that both sides of the synapse contribute to the effects of BDNF (Gartner et al., 2006; Gruart et al., 2007). The role of TrkB coupling to PLCg in LTP induced by high-frequency stimulation correlates with a role of this signalling pathway in associative learning (Gruart et al., 2007). 2.3. TrkB receptors and synaptic plasticity in other brain regions In addition to the effects in the hippocampus, TrkB receptors are also involved in synaptic plasticity in other brain regions. The amygdala is a brain region that plays an important role in acquisition, storage and expression of fear memory (Davis, 1997; Fendt and Fanselow, 1999). Fear conditioning, a simple model of associative learning, induces LTP in the lateral amygdala neurons (McKernan and Shinnick-Gallagher, 1997; Rogan et al., 1997). Studies performed using different fear conditioning protocols showed an upregulation of BDNF expression and TrkB receptor activation in the lateral amygdala, and inhibition of the TrkB signaling, with intra-amygdala infusion of a TrkB chemical inhibitor or by expressing a dominant-negative TrkB isoform, disrupted the acquisition of fear conditioning (Ou et al., 2010; Rattiner et al., 2004a,b). Altogether these results indicate that TrkB receptors play a role in this form of synaptic potentiation, and pharmacological studies showed that the PI3-K/Akt pathway contributes to LTP in the amygdala and to the consolidation of amygdala-dependent cued fear conditioning in rats (Lin et al., 2001). The same experimental approach showed a role for the Ras/ERK and PI3-K pathways in the acquisition of fear learning through recruitment of the Shc adaptor protein to activated TrkB receptors (Ou and Gean, 2006). In contrast, studies with genetic mouse models showed that PLCg mediates the TrkB-dependent acquisition of fear conditioning and amygdalar synaptic plasticity at the lateral and basolateral synapses, whereas the PI3K/Akt pathway contributes mainly to the consolidation of amygdala-dependent cued fear conditioning and LTP at the lateral synapses (Musumeci et al., 2009). Since no relevant abnormalities were found in the genetic mouse models used in this study it remains to be determined whether the discrepancy between these findings and those obtained with a pharmacological approach are due to non-specific effects of the chemical inhibitors used. BDNF–TrkB signaling activity also contributes to synaptic plasticity in the nucleus accumbens (NAc)-ventral tegmental area (VTA), a region that processes reward information. In this case BDNF released from NAc neurons was suggested to alter structural plasticity within the NAc-VTA circuit, thereby promoting the development and persistence of addictive behaviors (Graham et al., 2007, 2009; McGinty et al., 2010; Russo et al., 2009).

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3. Transcription- and translation-independent synaptic regulation by BDNF BDNF exerts fast effects on synaptic transmission by posttranslational modifications of synaptic proteins, both at the preand post-synaptic levels [e.g. (Levine et al., 1995; Lohof et al., 1993)]. Thus, BDNF-induced activation of TrkB receptors increases depolarization-evoked release of glutamate from isolated hippocampal and cerebrocortical nerve terminals (Jovanovic et al., 2000; Pascual et al., 2001; Pereira et al., 2006; Simsek-Duran and Lonart, 2008). Furthermore, the neurotrophin rapidly enhances the frequency of miniature excitatory post-synaptic currents in dissociated cultures of hippocampal neurons, further suggesting a pre-synaptic effect on glutamate release (Lessmann and Heumann, 1998; Li et al., 1998; Schinder et al., 2000; Tyler and Pozzo-Miller, 2001). Additional studies using hippocampal slices showed that BDNF acts on a rapid recycling pool of synaptic vesicles increasing the probability of neurotransmitter release, but in this case long stimulation periods were used and, therefore, transcription/translation-dependent mechanisms may also be involved (Tyler and Pozzo-Miller, 2001; Tyler et al., 2006). The role of BDNF as a retrograde messenger to potentiate glutamatergic synaptic transmission was also shown at a single cell level in cultured hippocampal neurons (Magby et al., 2006). The rapid effects of BDNF on neurotransmitter release are mediated, at least in part, by protein phosphorylation, downstream of TrkB receptor activation. The potentiation of glutamate release by BDNF is abrogated in cerebrocortical synaptosomes prepared from Synapsin I and Synapsin II deficient mice (Jovanovic et al., 2000). This protein is associated with the membrane of small synaptic vesicles and is a substrate of the ERK signaling pathway (Jovanovic et al., 2000), and phosphorylation of synapsins leads to detachment of synaptic vesicles from actin filaments near the presynaptic membrane, increasing the probability of exocytosis. Therefore, synapsin phosphorylation following stimulation of TrkB receptors may increase the docking of small synaptic vesicles thereby increasing glutamate release (Tartaglia et al., 2001). The Rab3a signaling pathway may also be targeted by BDNF to modulate glutamate release since cultured neurons isolated from Rab3a knockout mice do not show BDNF-induced enhancement of neurotransmitter release (Alder et al., 2005; Thakker-Varia et al., 2001). Similar findings were reported in nerve endings isolated from the CA1 region of mice deficient in Rim1a (Rab3 interacting molecule 1a), an effector molecule of Rab3a signaling necessary for L-LTP (Huang et al., 2005). Taken together these evidences suggest that BDNF may act in LTP, in part, by inducing the phosphorylation of pre-synaptic regulators of the exocytotic machinery, thereby increasing glutamate release. BDNF was also shown to upregulate the synaptic proteins synaptophysin and synaptobrevin in cultured hippocampal slices by mechanisms independent of translation that remain to be identified (Tartaglia et al., 2001). Protein phosphorylation may also account for some of the early post-synaptic effects of BDNF in the potentiation of glutamatergic synapses. Accordingly, stimulation of cultured hippocampal neurons with BDNF increases NMDA receptor single channel open probability (Levine et al., 1998), presumably through phosphorylation of the receptor subunits. BDNF was shown to induce tyrosine phosphorylation of GluN1 and GluN2B NMDA receptor subunits in cultured hippocampal neurons (Lin et al., 1998; Suen et al., 1997), and the effects of the neurotrophin on the electrophysiological properties of the receptor depend on the GluN2B subunits (Levine and Kolb, 2000). Studies performed in cultured organotypic hippocampal slices treated with BDNF also showed a rapid synaptic delivery of GluA1-containing AMPA receptors which was dependent on the activation of Trk (presumably TrkB)

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receptors (Caldeira et al., 2007a). The synaptic delivery of GluA1 receptor subunits induced by BDNF was also correlated with an increase in receptor phosphorylation (Caldeira et al., 2007a). Similarly, immunocytochemistry experiments in cultured cerebrocortical neurons showed that BDNF induces synaptic delivery of GluA1-containing AMPA receptors to the synapse from a local pool (Nakata and Nakamura, 2007). In addition to the effects in the distribution of receptors at the synapse BDNF may also contribute to structural plasticity. Studies with hippocampal slices showed an enhancement of spine labeling with phalloidin, a marker of F-actin, when BDNF was applied together with threshold level of theta-burst stimulation (Rex et al., 2007). Furthermore, chelation of BDNF with TrkB-Fc prevented the increase in F-actin resulting from suprathreshold levels of thetaburst stimulation. This suggests that BDNF may act as a regulator of actin dynamics in spines, and this effect may be mediated by an increase in the phosphorylation of p21-activated kinase and cofilin (Rex et al., 2007). A recent study showed that BDNF also activates m-calpain by ERK-dependent phosphorylation, mainly in dendrites and spines of hippocampal neurons, and this effect was also associated with actin polymerization (Zadran et al., 2010). These evidences suggest that calpain activation, and the consequent cleavage of synaptic proteins, may contribute to the role of BDNF in synaptic potentiation. The BDNF-induced pre- and post-synaptic changes described above, mediated by post-translational modifications of pre-existing proteins, are faster than those arising from protein synthesis. However, the changes induced by protein phosphorylation are likely not to last so long due to the activity of protein phosphatases. 4. Regulation of the translation machinery by BDNF The translation of a given mRNA requires three steps: initiation, elongation and termination. The initiation and elongation steps are considered to be rate-limiting (Herbert and Proud, 2007) and, therefore, subjected to regulation. For initiation to begin the complex eukaryotic initiation factor (eIF) 4F has to be formed in order to recruit both the ribosome and the mRNA molecule. The eIF4F complex is comprised by three subunits with specific functions: eIF4E binds to 50 capped mRNAs; eIF4A unwinds the secondary structure of the mRNA; eIF4G bridges the mRNA to the 43S pre-initiation complex. The assembly of eIF4F is modulated by eIF4E-binding proteins (4EBPs). Non-phosphorylated 4EBPs bind to eIF4E suppressing translation, whereas phosphorylation of 4EBPs induces eIF4F complex formation and translation activation. Several studies show that synaptic plasticity is associated with an increase in phosphorylation of 4EBPs as well as eIF4E itself (Richter, 2007). Once initiation is completed elongation factors are recruited, including the elongation factor eEF2, which promotes the GTP-dependent translocation of the nascent protein chain from the A-site to the P-site of the ribosome. The activity of 4EBPs, eIF4E and eEF2 is regulated by different signaling pathways, including the ERK, PI3-K and mTOR (mammalian target of rapamycin) pathways (Inamura et al., 2005; Kelleher et al., 2004; Takei et al., 2001, 2009; Tang et al., 2002). In cultured cortical neurons BDNF induces protein expression by regulating translation initiation and elongation steps, through a mechanism dependent on the activation of mTOR, PI3-K and ERK downstream cascades (Takei et al., 2001) (Fig. 1). BDNF promotes the phosphorylation of eIF4E and its binding protein-1 (4EBP1), by mechanisms sensitive to chemical inhibitors of the ERK and PI3-K signaling pathways, respectively, and the phosphorylation of 4EBP1 is mediated by activation of the mTOR pathway (Takei et al., 2004). Similarly, infusion of BDNF in the hippocampal dentate gyrus to induced LTP (BDNF-LTP) also increases eIF4E phosphorylation (Kanhema et al., 2006). The mTOR cascade regulates both the

50 cap-dependent translation, by inducing eIF4F complex formation, and the 50 TOP containing mRNAs, by activating the S6 kinase pathway. Additional studies using cultured cerebrocortical neurons and synaptoneurosomes isolated from the cerebral cortex, a subcellular fraction containing the pre- and post-synaptic regions, showed that BDNF induces the phosphorylation of 4EBP1 in dendrites, by a rapamycin-sensitive mechanism, lifting the blockage on eIF4E and therefore initiating translation (Takei et al., 2004). Recent studies using cultured cerebrocortical neurons also showed that TrkB receptor activation by BDNF mediates the effect of ampakines (AMPA receptor positive modulators) on mRNA translation (Jourdi et al., 2009). Under these conditions translation activation is triggered by the mTOR pathway and is mediated by phosphorylation of 4EBP1. The initiation step of translation also depends on eIF2, which is necessary to assemble the eIF2.GTP.Met.tRNAi complex (Rhoads, 1999), and for priming each 40S ribosomal subunit. The activity of eIF2 is regulated by the guanine nucleotide exchange factor eIF2B, which catalyzes the exchange eIF2.GDP to eIF2.GTP. In cultured cerebrocortical neurons BDNF was found to activate glycogen synthase kinase activity which stimulates eIF2B by phosphorylation (Takei et al., 2001). Accordingly, BDNF was also found to upregulate eIF2 activity, which should contribute to translation activity. In addition to the effects on translation initiation, BDNF also affects protein synthesis at the elongation step. Local infusion of BDNF into the dentate gyrus of anesthetized rats to induced LTP (BDNF-LTP) promoted a rapid and transient increase in eEF2 phosphorylation (Kanhema et al., 2006), which is expected to reduce ribosome binding and decrease global protein synthesis (Nairn and Palfrey, 1987; Ryazanov et al., 1988). Interestingly, these effects of BDNF on eEF2 phosphorylation, mediated by ERK, were not observed in synaptoneurosomes isolated from the same brain region (Kanhema et al., 2006), suggesting that the transient arrest of elongation may be limited to non-synaptic sites. In synaptic regions BDNF induces eIF4E phosphorylation, and therefore, this is a privileged environment for translation activity induced by the neurotrophin. Translation of specific mRNAs (e.g. Arc and CaMKIIa) may still occur in non-synaptic regions despite the arrest in global translation, by a mechanism that is 50 capindependent and mediated by IRES [internal ribosomal entry site; reviewed in (Costa-Mattioli et al., 2009)], although this is a less frequent process. The observed effects of BDNF in eEF2 phosphorylation in the hippocampal dentate gyrus contrast with the results obtained in cultured cerebrocortical neurons subjected to acute or chronic stimulation with BDNF, and with the evidences obtained in BDNF transgenic and knock-out mice, which suggest that in the cerebral cortex the neurotrophin upregulates the active, nonphosphorylated form of eEF2 (Inamura et al., 2005; Takei et al., 2009). Altogether these evidences suggest that the mechanisms controlling the direction of eEF2 phosphorylation and translation activity by BDNF are compartment-specific. The phosphorylation of this elongation factor is also stimulus specific as, for example, action potential-dependent synaptic activity induces eEF2 dephosphorylation in cultured hippocampal neurons, while spontaneous activity enhances phosphorylation, suppressing its activity and therefore constraining local translation (Sutton et al., 2007). The effect of BDNF on de novo total protein synthesis has been investigated in cultured neurons and in isolated synaptic fractions, using radiolabelled amino acids, but conflicting results were obtained. BDNF was shown to increase protein synthesis in cultured cerebrocortical neurons (Takei et al., 2001, 2009), but no significant effect was observed in similar studies conducted in cultured hippocampal neurons and in synaptoneurosomes (Manadas et al., 2009; Yin et al., 2002). Most likely, BDNF plays a specific and direct effect on a subset of proteins rather than having a

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Fig. 1. Regulation of translation by BDNF. Activation of TrkB receptors stimulates the PI3-K and the ERK signaling pathways. ERK stimulates translation activity by regulating the eIF4F complex, possibly through phosphorylation of eIF4E. This signaling pathway may also lead to phosphorylation (and activation) of eIF4B, as shown in the response to activation of other tyrosine kinase receptors (Shahbazian et al., 2006). Activation of Akt, downstream of the PI3-K, stimulates translation by two different mechanisms, through the eIF4F complex (50 CAP mRNAs) and the S6 kinase (50 TOP mRNAs). The 4EBP1 is an Akt and ERK substrate, and is regulated by mTOR. The phosphorylated form of the protein does not bind to the eIE4E and, therefore, has no effect on translation activity. Furthermore, BDNF activates EF2 through dephosphorylation of the elongation factor, thereby modulating the translation of the nascent protein. Some components of the pathway are not shown to simplify the diagram.

general effect on neuronal proteome. In a proteomics study where the effect of BDNF on the proteome of cultured hippocampal neurons was resolved by 2D-gel electrophoresis, the neurotrophin was shown to change the abundance (up- or down-regulate) of components of (i) Nucleobase, nucleoside, nucleotide and nucleic acid metabolism, (ii) protein metabolism, (iii) carbohydrate metabolism, (iv) regulators of apoptosis, and (v) regulators of cell proliferation (Manadas et al., 2009). Among the proteins identified were components belonging to the translation machinery, as well as proteins of the ubiquitin proteasome system, suggesting that BDNF regulates not only translation but also protein degradation. Interestingly, protein degradation by the proteasome was shown to be relevant in LTP [(Dong et al., 2008; Fonseca et al., 2006); reviewed in (Steward and Schuman, 2003)]. Since the above mentioned proteomics study was not conducted in the presence of transcription inhibitors it is not possible to conclude about the relative role of transcription vs. direct translation regulation in the observed effects. The BDNF-induced rapid changes in the synaptic proteome (presumably post-synaptic) were investigated in cultured cerebrocortical neurons using a multidimensional protein identification technology (MudPIT) and relative quantification by spectra counting. Synaptoneurosomes were isolated 30 min after stimulation with BDNF and, therefore, the observed changes in the proteome were proposed to arise from local protein synthesis. The proteins identified belong to different categories, including translation factors, mRNA processing enzymes, proteins involved

in synaptic structure and vesicle formation, among others (Liao et al., 2007). This study further indicates that BDNF acts locally in the regulation of translation, and the observed inhibitory effects of rapamycin show that the alterations in the synaptic proteome are mediated by the mTOR pathway. 5. Dendritic transcripts regulated by BDNF 5.1. Dendritic transcripts One of the mechanisms of regulation of protein synthesis by BDNF at synapses relies on the selective targeting of mRNAs to dendrites (Fig. 2). The most common difficulties in the identification of dendritic transcripts are contamination with somatic material and the low sensitivity of the methods used. Furthermore, the use of different cell types and distinct neuronal development stages may also make difficult the comparison between the results available in the literature. Thus, a microarray study using the dissected outer stratum radiatum (dendritic lamina) from the rat hippocampal CA1 region allowed identifying 154 putative dendritic transcripts, including ribosomal proteins, translation factors and RNA-binding proteins (Zhong et al., 2006). A distinct complement of dendritic transcripts was identified in a study where hippocampal neurons were cultured on polycarbonate filters that allow a physical separation of axons and dendrites from cell bodies. The dendritic transcriptome was analyzed combining microarray and in situ hybridization techniques, and

[(Fig._2)TD$IG]

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Fig. 2. BDNF regulates glutamatergic synaptic transmission by acting at the pre- and post-synaptic level. BDNF sequestered in secretory vesicles present in the post-synaptic region is released by a Ca2+-dependent mechanism, following activation of glutamate receptors. BDNF acts on pre-synaptic TrkB receptors, potentiating glutamate release, and exerts short- and long-term effects in the post-synaptic cell. BDNF induces the translocation of AMPA receptors to the synapse and increases the activity of NMDA receptors by phosphorylation-dependent mechanisms. Furthermore, BDNF induces local protein synthesis at the synapse from mRNAs transported along dendrites in RNA granules, by promoting the disassembly of the granules (1) and activating the translation machinery (2). Additional effects of BDNF include the regulation of RNA transport along dendrites, which is mediated by kinesin motor proteins, and activation of gene expression (3).

the results showed over 100 potentially localized mRNAs, mainly coding for proteins belonging to the translation machinery (Poon et al., 2006). However, in contrast with the results obtained for the CA1 stratum radiatum, no transcripts coding for proteins related with cell adhesion, protein degradation and membrane trafficking were identified in the neurites of cultured hippocampal neurons. Surprisingly, several mRNAs with known dendritic localization were not identified in the aforementioned microarray studies, such as mRNAs for CaMKIIa (Burgin et al., 1990), BDNF and TrkB (Tongiorgi et al., 1997), and Arc (Ying et al., 2002). However, since the Arc and BDNF mRNAs are targeted to dendrites in an activitydependent manner, their dendritic expression was probably below the threshold for detection under the experimental conditions used (Bramham et al., 2010; Steward et al., 1998; Tongiorgi et al., 2004; Tongiorgi and Baj, 2008). 5.2. BDNF and local translation at the synapse The effect of BDNF on the abundance of dendritic mRNAs for components of the translation machinery was investigated in cultured hippocampal neurons using the culture system that allows a physical separation of neurites from cell bodies (Manadas et al., 2009; Poon et al., 2006). The results showed differential effects of the neurotrophin in the dendritic expression of

transcripts for initiation and elongation factors, aminoacyl-tRNA synthases and other translation related proteins (Table 1), and the effects not always matched the alterations in the cell soma, pointing out the compartment-specificity of BDNF actions. The regulation of the dendritic expression of these mRNAs by BDNF, and the upregulation of the translation machinery by the neurotrophin at the synapses (Liao et al., 2007), may act together to promote local protein synthesis, using pre-existing mRNAs and/ or transcripts delivered to dendrites after stimulation. The mRNAs for BDNF and its receptor TrkB are present in the proximal region of the dendrites of cultured hippocampal neurons and their distribution is further extended towards the distal region upon membrane depolarization by a PI3-K-dependent mechanism (Righi et al., 2000; Tongiorgi et al., 1997). Although two BDNF transcripts are found in the brain, with short or long 30 untranslated regions, only the latter is targeted to dendrites in cultured hippocampal neurons, contributing to the pruning and enlargement of dendritic spines, and to LTP (An et al., 2008). Neuronal activity induced by chemical inhibitors of the GABAergic synaptic transmission also upregulates local protein synthesis in dendrites in hippocampal cultures, including BDNF, by a mechanism dependent on eEF2 phosphorylation (Verpelli et al., 2010). Furthermore, a significant increase in the mRNA for BDNF was observed in the hippocampal laminae containing the apical

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Table 1 Dendritic targets of BDNF.

Proteins with known dendritic functions

Components of the translation machinery

Protein ID

Experimental approaches used

Cell type

Preparation

Reference

CamKIIa

Time-lapse imaging Analysis of polysome fraction

Hippocampal neurons

Isolated dendrites Slices

(Aakalu et al., 2001) (Shiina et al., 2005)

Arc

qPCR

Cortical and hippocampal neurons

Synaptoneurosomes

(Ying et al., 2002)

BDNF TRK B

Analysis of polysome fraction

Hippocampal neurons

Slices

(Shiina et al., 2005)

Homer2 NR1 DLG2 LIMK-1

Analysis of polysome fraction using microarrays

Cortical neurons

Synaptoneurosomes

(Schratt et al., 2004)

Aminoacyl-tRNA Other translation components

qPCR

Hippocampal neurons

Physically separated dendrites

(Manadas et al., 2009)

Elongation factors Initiation factors Ribossomal proteins

MudPIT

Cortical neuron

Synaptoneurosomes

(Liao et al., 2007)

dendrites of pyramidal neurons and granule cells of rats treated with pillocarpine to induce status epilepticus (Tongiorgi et al., 2004). The delivery of BDNF and TrkB mRNAs to the distal regions of dendrites induced by neuronal activity may upregulate BDNF signaling under these conditions. The first direct evidence for a role of BDNF in the induction of protein synthesis in dendrites came from studies using a reporter in which GFP was flanked by 50 and 30 untranslated (UTR) regions from the CaMKIIa (Aakalu et al., 2001). To identify the mRNAs that are translated in response to stimulation with BDNF in mature cultured cerebrocortical neurons, the mRNA content associated to a polyribosome fraction, indicating their commitment to translation, was identified by microarray analysis. Interestingly, BDNF promotes translation of 143 mRNAs, 48 of them by a mechanism dependent on the PI3-K/mTOR pathway (Schratt et al., 2004). This study showed that the translation of CaMKIIa and NMDA receptor subunit 1 (GluN1) mRNAs is regulated by BDNF in synaptoneurosomes, confirming the dendritic localization of both transcripts (Burgin et al., 1990; Gazzaley et al., 1997). Moreover, BDNF stimulation also recruited to polyribosome fractions the mRNAs for Homer2, a member of the Homer family of post-synaptic scaffolding proteins (Shiraishi-Yamaguchi and Furuichi, 2007), and for the AMPA receptor subunit GluA1. The increase in translation of both Homer2 and GluA1 induced by BDNF was further confirmed using synaptoneurosomes, and was shown to be rapamycin-sensitive (Schratt et al., 2004), indicating that the transcripts are targeted to the synapse and translated locally in response to stimulation with the neurotrophin. In addition to the local synthesis of GluA1 containing AMPA receptors, BDNF also induces the delivery of these receptors to the synapse (Caldeira et al., 2007a; Li and Keifer, 2009; Nakata and Nakamura, 2007), thereby contributing to synaptic strengthening. Taken together the available evidences point to a role of BDNF in the regulation of the trafficking of several mRNAs in dendrites, which together with the changes in the translation machinery at the synapse contribute to local changes in the proteome and regulation of the post-synaptic response. Interestingly, some of the transcripts that are translated at the synapse in response to BDNF stimulation code for neurotransmitter receptors and proteins that control their distribution in the excitatory synapse. The local synthesis of these synaptic components may contribute to the synaptic specificity of LTP. Arc (activity-regulated cytoskeleton-associated protein) is an immediate early gene that plays an important role in synaptic

plasticity in the hippocampus. The protein is robustly induced by plasticity-inducing stimulation, and Arc knockout mice show defects in LTP maintenance and in memory storage [(Plath et al., 2006); reviewed in (Bramham et al., 2010)]. Stimulation of cerebrocortical and hippocampal synaptoneurosomes with BDNF upregulates Arc protein levels, by a mechanism dependent of NMDA receptor activation (Yin et al., 2002), showing that the protein can be translated locally at the synapse. In vivo stimulation of the dentate gyrus with BDNF, which leads to LTP, is also associated with dendritic transport of Arc mRNA and upregulation of Arc protein levels in granule cells by a mechanism dependent on ERK activation and CREB (Ying et al., 2002). Synaptic strengthening in this paradigm is completely reversed by the injection of Arc antisense (ARC AS), correlating with a decline in mRNA and Arc protein observed in the molecular layer. Moreover, early inhibition of Arc synthesis blocked the early but not the late phase of LTP, suggesting Arc as an important player in a time-dependent consolidation of BDNF-LTP (Messaoudi et al., 2007). Additional studies have shown that Arc transcripts are rapidly target to dendrites and translated in response to neuronal activity [(Steward et al., 1998); for a recent review see also (Bramham et al., 2010)], implying an important role in plasticity. These findings contrast with the results showing no Arc mRNA in the group of transcripts recruited for translation following stimulation of cerebrocortical neurons with BDNF (Schratt et al., 2004). This discrepancy suggests that BDNF may be preferentially coupled to the translation of Arc mRNA at the synapse and, therefore, the effects are less significant when total cell translation activity is analyzed. Arc may contribute to synaptic potentiation by inducing the dephosphorylation of cofilin, one of major regulators of F-actin dynamics in spines. Studies on the BDNF-LTP in the dentate gyrus showed a decrease in cofilin phosphorylation in the presence of Arc AS, which causes a rapid reversal of synaptic potentiation. Thus, Arc couples the induction of gene expression to F-actin expansion, which may ultimately lead to morphological changes (Matsuzaki et al., 2004; Tanaka et al., 2008) in BDNF-induced LTP (Messaoudi et al., 2007). Since local F-actin formation is required for targeting Arc mRNA to active synapses (Huang et al., 2007), this may be relevant in LTP induced by BDNF. Interestingly, BDNF was also shown to play a role in gradual spine enlargement in CA1 pyramidal neurons following repetitive pairing of post-synaptic spikes and two-photon uncaging of glutamate at single spines, a process that requires protein synthesis (Tanaka et al., 2008). Furthermore, a recent study showed that BDNF upregulates RhoA

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protein levels in synaptoneurosomes isolated from the mouse forebrain (Troca-Marin et al., 2010). RhoA is a member of the Rho GTPase family that is involved in the remodeling of actin cytoskeleton, but it remains to be determined whether the upregulation of this protein contributes to the effects of BDNF in synaptic plasticity. 5.3. Effects of BDNF on post-transcriptional modulators In addition to the effects on the proteome due to local regulation of the protein synthesis machinery, synaptic activity and changes in the extracellular environment may also act on posttranscriptional regulators, such as ribonucleoproteins (RNPs) and micro-RNAs (miRNAs), which ultimately can affect mRNA translation and stability. The latter mechanisms are likely to contribute to local effects of BDNF in the regulation of translation of specific mRNAs, since each RNP and miRNA target a particular set of mRNAs. However, up to now few studies have addressed the mechanisms whereby neuronal activity regulates locally these two mechanisms at synapse. Dendritic localized mRNAs are transported together with RNPs within RNA granules and actively trafficked to distal compartments by molecular motors, in a translational silent manner [Fig. 2; (Konecna et al., 2009)]. Therefore, RNPs play two important roles, as modulators of mRNA localization and as translational repressors. A recent study showed that BDNF, similarly to KCl depolarization, induces the translocation of dendritic-like P-bodies towards the distal region of the dendrites (Cougot et al., 2008). These neuronal RNA containing structures constitute a new class of RNP-particles with both similarities and differences to P-bodies of non-neuronal cells. Upon specific stimuli, RNPs repression is lifted and mRNAs become associated with polysomes where translation

[(Fig._3)TD$IG]

begins. RGN105 is a component of translational silent RNA granules and co-localizes with Staufen- and CaMKIIa mRNA positive RNA-granules in hippocampal neurons (Shiina et al., 2005). BDNF regulates the distribution of RGN105 in dendrites, promoting its release from RNA granules in parallel with an enrichment of CaMKIIa, BDNF, TrkB and CREB mRNAs in a polysome fraction, consistent with local translation (Fig. 3). In addition, phosphorylation of eIF4E was also observed under the same conditions, a hallmark of enhanced translation. How BDNF promotes the release of RGN105 from RNA granules is still not known, but it may arise from an alteration of affinity following RGN105 phosphorylation by kinases activated upon synaptic stimulation. MicroRNAs (miRNAs) are emerging as key synaptic modulators due to their role in local regulation of mRNA translation, and the modulation of their expression and function by neuronal activity. MiRNAs act by targeting partially complementary mRNAs leading to translation repression or mRNA degradation. In fact, miRNAs usually act by fine-tuning gene expression rather than as on–off switches, a feature important for mRNA regulation [reviewed in (Schratt, 2009)]. Several transcripts coding key synaptic components, including FMRP (fragile X mental retardation protein) and PSD95, are predicted targets of human miRNAs (John et al., 2004), supporting the hypothesis that miRNAs can play a regulatory role at the synapse. The pioneer study by Schratt et al. (2006) showed that microRNA-134 (miR-134) has a punctated distribution along dendrites, targeting the Lim-domain containing kinase (Limk1) mRNA, which encodes a kinase that promotes actin polymerization and spine growth through phosphorylation of cofilin. The interaction between miR-134 and the Limk1 mRNA may keep it silent while it is transported along dendrites towards the synapse. MiR134 regulates the size of dendritic spines during spine

Fig. 3. Regulation of local translation by BDNF through modulation of RNA-binding proteins. Activation of TrkB receptors by BDNF initiates several intracellular signaling cascades, including the mTOR pathway. In synaptoneurosomes BDNF was shown to release Limk1 mRNA from a translation repression state induced by miR-134, promoting its local translation. The mechanism by which BDNF induces Limk1 translation is not yet clear since miR-134 moves together with Limk1 mRNA to sites of active translation. Most likely, BDNF promotes the phosphorylation of a yet unknown factor leading to the disassembling of the silencing complex (SC). In addition, RG105-containg granules are regulated by BDNF promoting the redistribution of target mRNAs (CaMKIIa, BDNF, TrkB) to nearby polysomes. Another evidence for the central role of BDNF in local translation was shown by the regulation of the FMRP–CYFIP1–eIF4E complex. BDNF decreases the interaction of CYFIP1 with eIF4E, possibly by phosphorylation, releasing the initiation factor and increasing synaptic translation of FMRP target mRNAs. During dendritic maturation, BDNF decreases Pumilio2 (Pum2) mRNA by inducing the transcription of miR-134 (part of the cluster miR 379-410) in a Mef2-dependent manner. This effect of the neurotrophin on Pum2, by means of miR-134, induces the redistribution of Pum2 target mRNAs to the local protein synthesis machinery. (Note: For convenience of diagram simplicity the TrkB receptor was placed near the nucleus, but is not clear which TrkB receptor population is activated).

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development, possibly by recruiting a silencing complex that may prevent Limk1 mRNA translation. The release of BDNF and consequent activation of post-synaptic receptors following synaptic stimulation may inactivate the silencing complex, allowing Limk1 protein synthesis. The kinase promotes actin polymerization and spine growth through phosphorylation of cofilin and accordingly, Limk1 knockout mice exhibit abnormalities in dendritic spine structure similar to those observed in hippocampal neurons overexpressing miR-134 (Meng et al., 2002). Interestingly, miR-134 continues to bind Limk1 mRNA while moving to the polysome fraction, suggesting that BDNF may increase Limk1 expression through other translation effectors [Fig. 3; (Schratt et al., 2006)]. The expression of miRNA is also regulated by neuronal activity, providing an additional level of translation regulation. Thus, KCl depolarization of cultured hippocampal neurons increases miR134 levels by a mechanism dependent on Mef2 (myocyte enhancing factor 2), a transcription factor that promotes dendritogenesis and negatively regulates synapse number. Similar results were described for neurons stimulated with BDNF, and the dendritic miR-134 was shown to promote dendritogenesis through down-regulation of the Pumilio2 (Pum2) mRNA (Fiore et al., 2009). Pum2 is a RNA-binding protein present in RNA granules, which modulates dendritic morphogenesis and synaptic function in mature hippocampal neurons by suppressing eIF4E translation (Vessey et al., 2010). The BDNF-induced downregulation of Pum mediated by miR-134 may promote the redistribution of Pum mRNA targets, releasing them for local translation. Therefore, miR134 may play a central role by acting as a buffer that regulates important factors during dendritogenesis. Indeed, BDNF-induced transcription of miR-134 fine-tunes Pum2 expression throughout the cell, while its repression at dendrites upon stimulation with the neurotrophin induces Limk1 expression. The translation of some dendritic mRNAs, including the transcripts for CaMKIIa and Limk1, is also inhibited by the RNAinduced silencing complex (RISC) protein MOV10 in cultured hippocampal neurons. Upon synaptic activation MOV10 is degraded by the proteasome thereby relieving the suppression of translation (Banerjee et al., 2009). Since BDNF is known to regulate both CaMKIIa and Limk1 local translation it would be interesting to determine whether BDNF plays a role locally in the regulation of Pum2 and MOV10 function at the synapse. In addition to the effects on miR-134, neurotrophins also regulate other miRNAs, and altogether this may provide a mechanism of fine-tuning the expression of proteins. Thus, BDNF induces the transcription of miR-132 and miR-212 through activation of ERK and the calcium response element binding protein (CREB) in cerebrocortical neurons. MiR-132 is required to inhibit translation of P250GAP, a GTPase-activating protein, enhancing dendritic growth (Remenyi et al., 2010; Vo et al., 2005). Another key player implicated in mRNA translation is the FMRP, the absence of which causes the Fragile X Syndrome (FXS), the most common inherited cause of mental retardation, characterized by deficits in learning and memory (Bagni and Greenough, 2005). FMRP contains multiple RNA-binding domains and is widely thought to function as a translational suppressor of specific mRNAs, including MAP1b, CaMKIIa, and Arc (Bassell and Warren, 2008). Furthermore, FMRP interacts with two microRNAs with opposing effects on dendritic spine morphology and synaptic physiology in hippocampal neurons, miR-125b and miR-132 (Edbauer et al., 2010). It was suggested that miR-125b may act together with FMRP in the regulation of GluN2A translation at specific subcellular locations and this effect may be relevant in synaptic plasticity. However, since no changes in total GluN2A protein levels were found in the hippocampus of FMR1 KO mice, this is likely not to account for the observed upregulation of this

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NMDA receptor subunit in hippocampal neurons treated with BDNF (Caldeira et al., 2007b). FMRP may also regulate translation through interaction with the cytoplasmic FMRP interacting protein 1 (CYFIP1/Sra1), a protein that binds directly the cap-binding factor eIF4E and forms a complex with FMRP-target mRNAs (Napoli et al., 2008). Brain cytoplasmic RNA 1 (BC1), another FMRP binding partner [however, see (Iacoangeli et al., 2008) for conflicting results], further increases the affinity of FMRP for the eIF4E–CYFIP1 complex. The complex formed by eIF4E–CYFIP1–FMRP is found at the synapse in cultured cerebrocortical neurons, and it was proposed that FMRP may act by recruiting CYFIP1 on the 50 end of interacting mRNAs to repress translation. Stimulation of cultured cerebrocortical neurons and synaptoneurosomes with BDNF dissociates eIF4E and CYFIP1, and releases the associated RNAs, and this may allow initiating translation (Napoli et al., 2008). The Fmr1 knockout mouse model of FXS is also characterized by a decrease in the interaction of target mRNAs with CYFIP1, enhancing the translation of MAP1B, APP and CaMKIIa. Furthermore, these mice present abnormal synaptic spines, which are more dense, longer and thinner than those of the wild-type animals, resembling immature spines (Bagni and Greenough, 2005), suggesting that FMRP1 is involved in repressing the translation of proteins regulating synapse maturation. Furthermore, FMRP binds mRNAs encoding several PSD components, including Shank1, SAPAP1-3, PSD95 and the glutamate receptor subunits GluN1 and GluN2B (Schutt et al., 2009), and was shown to affect the translation of Shank1 (Schutt et al., 2009). Considering all these roles played by FMRP it is not surprising that deletion of the protein in FXS is associated with structural alterations in dendritic spines and mental retardation [(Bakker et al., 1994; Marin-Padilla, 1972; Purpura, 1974); for a review see also (Bagni and Greenough, 2005)]. 6. Conclusion Although it is well established that several activity-induced paradigms can induce local mRNAs translation, additional studies are still required to fully elucidate how different mRNAs are transported and anchored at specific sites along dendrites. Evidences from several studies have shown a great variability in the composition of RNA granules, mainly due to differences between cell type and maturation state. The present challenge is to understand how the specificity of mRNAs/RNPs is achieved in each cell type. In particular, it will be important to establish the role of BDNF in the regulation of mRNAs transport and local translation, particularly in physiological environments, and identify the contribution to synaptic plasticity. Acknowledgements The work in the authors laboratory is funded by Fundac¸a˜o para a Cieˆncia e a Tecnologia and FEDER, Portugal (PTDC/SAU-FCF/72283/ 2006 and POCTI/SAU-NEU/104297/2008). References Aakalu, G., Smith, W.B., Nguyen, N., Jiang, C., Schuman, E.M., 2001. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 30, 489–502. Aicardi, G., Argilli, E., Cappello, S., Santi, S., Riccio, M., Thoenen, H., Canossa, M., 2004. Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 101, 15788–15792. Alder, J., Thakker-Varia, S., Crozier, R.A., Shaheen, A., Plummer, M.R., Black, I.B., 2005. Early presynaptic and late postsynaptic components contribute independently to brain-derived neurotrophic factor-induced synaptic plasticity. J. Neurosci. 25, 3080–3085.

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