BDNF mechanisms in late LTP formation: A synthesis and breakdown

Neuropharmacology xxx (2013) 1e13

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Invited review

BDNF mechanisms in late LTP formation: A synthesis and breakdown Debabrata Panja a, b, Clive R. Bramham a, b, * a b

Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 May 2013 Received in revised form 21 June 2013 Accepted 23 June 2013

Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (LLTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research. This article is part of a Special Issue entitled ‘BDNF’. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Brain-derived neurotrophic factor (BDNF) TrkB signaling Synaptic plasticity Long-term potentiation (LTP) Protein synthesis Translation control Cytoskeletal dynamics

1. Introduction The compartmentalization of electrical and biochemical signals in dendritic spines makes glutamatergic synapses a natural locus

Abbreviations: Arc, activity-regulated cytoskeleton-associated protein; AS, Angelman syndrome; AS-ODN, antisense oligodeoxynucleotide; BDNF, brainderived neurotrophic factor; CA, cornu ammonis; CaMKII, Ca2- and calmodulindependent protein kinase II; cdk, cyclin-dependent kinase; CREB, cAMP response element-binding protein; CYFIP, cytoplasmic FMRP-interacting protein; DG, dentate gyrus; DSCR, Down syndrome critical region; 4EBP, eIF4E-binding protein; eEF, eukaryotic elongation factor; eIF, eukaryotic initiation factor; E-LTP, early-LTP; FMRP, fragile X mental retardation protein; GAB1, Grb2-associated binding protein 1; GFP, green-fluorescent protein; HFS, high-frequency stimulation; hnRNP, heterogenous nuclear ribonucleoprotein; IEG, immediate-early gene; IP3, inositol 1,4,5trisphosphate; LIMK1, LIM domain kinase 1; L-LTP, late-LTP; LTD, long-term depression; LTP, long-term potentiation; MAP, microtubule-associated protein; MEK1/2, MAPK and ERK kinase, type 1/ 2; miRNA, microRNA; MNK, MAP-kinase interacting kinase; mTOR, mammalian target of rapamycin; PAK, p21-activated kinase; PDZ, postsynaptic density-95/Discs large/zona occludens-1; PI3-K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PKM, protein kinase M; PRP, plasticity-related protein; PSD, postsynaptic density; PSD95, postsynaptic density protein 95; PSI, protein synthesis-inhibitor; RISC, RNA-induced silencing complex; S6K, p70 S6 kinase; TBS, theta-burst stimulation; TORC, target of rapamycin (TOR) complex; TSC, tuberous sclerosis protein; TrkB, tropomyosin-related kinase B; YFP, yellow fluorescent protein; ZIP, zeta inhibitory peptide. * Corresponding author. Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. Tel.: þ47 55 58 60 32; fax: þ47 55 58 64 10. E-mail address: [email protected] (C.R. Bramham).

for encoding information in neural networks. Hence, activitydependent forms of synaptic plasticity, such as long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity (scaling), are of immense interest for elucidating the molecular mechanisms of memory formation, storage, and forgetting. Stable, late phase LTP (L-LTP) is associated with enlargement and remodeling of the postsynaptic density (PSD), enlargement of pre-existing dendritic spines, as well as de novo synapse formation (Lisman and Raghavachari, 2006; Bourne and Harris, 2008). Such large-scale growth and remodeling is thought to require de novo synthesis of synaptic proteins, along with protein trafficking and degradation. The secretory peptide, brain-derived neurotrophic factor (BDNF), plays a critical role in stimulating the formation of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms by which BDNF promotes L-LTP have not been established for any specific brain region. Glutamatergic synapses are capable of expressing mechanistically distinct forms of LTP, and glutamatergic synapses differ in morphology, physiology, and molecular composition between brain regions and between synapses on the same neuron. With a focus on how BDNF signaling controls L-LTP, we distill and discuss the latest advances along three main lines: 1) tropomyosin-like kinase B (TrkB) receptor-coupled translational control underlying local protein synthesis and L-LTP, 2) mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-

0028-3908/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

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TrkB regulation of dendritic spine cytoskeletal dynamics. Finally, we seek to understand the functional relationships between these mechanisms and outline the major outstanding issues. 2. BDNF as a trigger for protein synthesis-dependent late LTP Classically, LTP maintenance is split into early and late phases in which only the late, stable phase is blocked by protein synthesis inhibitors (PSIs) (Krug et al., 1984; Stanton and Sarvey, 1984; Frey et al., 1988; Otani et al., 1989; Matthies et al., 1990; Abraham and Williams, 2008; Mayford et al., 2012). As underscored by Routtenberg (2008), the use of PSIs to define the physiological role of protein synthesis has significant caveats. By rapidly inhibiting almost all cellular protein synthesis, it is not surprising that PSIs have deleterious impacts on cellular function that ultimately lead to apoptosis, even in the absence of any immediate effects of the drug on basal synaptic transmission. PSIs also have effects unrelated to their ability to inhibit protein synthesis. For example, intracerebral injection of anisomycin, one of the most commonly used PSIs, triggers acute enhancement of norepinephrine release, activation of p38 MAP kinase, and phosphorylation of cyclic AMP response element-binding protein (CREB) (Canal et al., 2007; Routtenberg, 2008). In recent years, however, the case for new protein synthesis as a mechanism for L-LTP formation has received strong support by convergent studies employing pharmacological and genetic manipulation of translation factors and the proximal signal transduction pathways (kinases/phosphatases) regulating these factors, combined with direct biochemical assays of translational activity as well as protein expression and in situ visualization of new protein synthesis (Costa-Mattioli et al., 2009; Sossin and Lacaille, 2010; GalBen-Ari et al., 2012; Darnell and Klann, 2013; Gkogkas et al., 2013; Santini et al., 2013). As discussed later on, evidence is still sparse when it comes to identifying causal roles of specific, synaptic activity-induced proteins in L-LTP formation. Local synthesis of proteins in neuronal dendrites contributes to synaptic homeostasis and plasticity. In response to synaptic inputs, the time, place, and amount of cellular protein synthesis may be finetuned (Bramham and Wells, 2007; Martin and Ephrussi, 2009). In the CA1 region of rat hippocampal slices, a requirement for local protein synthesis has been demonstrated for several forms of LTP in intact slices and slices in which the synaptic neuropil is physically separated from the CA1 and CA3 cell bodies (Kang and Schuman, 1996; Bradshaw et al., 2003; Huang and Kandel, 2005; Vickers et al., 2005). Mature BDNF is stored at glutamatergic synapses and released in response to stimulus bursts used to induce LTP (Hartmann et al., 2001; Aicardi et al., 2004; Kuczewski et al., 2009; Matsuda et al., 2009). There is anatomical and functional evidence supporting both presynaptic and postsynaptic storage and release of endogenous BDNF from glutamatergic synapses (Lessmann and Brigadski, 2009; Matsuda et al., 2009; Jakawich et al., 2010; Dieni et al., 2012), but the sites of BDNF release during LTP remain to be definitively established and likely differ between brain regions and LTP induction protocols. Previous reviews have detailed the permissive and instructive roles for BDNF in LTP induction and maintenance (reviewed in Bramham and Messaoudi, 2005; Minichiello, 2009; Waterhouse and Xu, 2009; Park and Poo, 2013). Here, we review the case for BDNF as a regulator of protein synthesis and protein synthesis-dependent L-LTP. The properties of L-LTP in the CA1 region and dentate gyrus as discussed in the review are summarized in Table 1. 2.1. BDNF and protein synthesis-dependent LTP To explore the time-window of TrkB activation in theta burst stimulation-induced LTP (TBS-LTP), Lu et al. (2011) used mice

harboring a serine to phenylalanine substitution in the ATP-binding pocket of kinase subdomain V of TrkB. The activation of TrkB receptors in these mice can be rapidly and reversibly blocked by 1NMPP1, a small molecule derivative of the kinase inhibitor PP1. The authors showed that late TBS-LTP in the CA1 region is blocked when hippocampal slices from these mice are perfused with 1NMPP1 from 1 to 40 min post-TBS, but are not affected by 1NMPP1 treatment thereafter. The BDNF scavenger, TrkB-Fc, has similarly been shown to inhibit late TBS-LTP when applied within 10 min of TBS (Rex et al., 2007). In contrast, high-frequency stimulation induced LTP (HFSLTP) in the CA1 of hippocampal slices can be inhibited by TrkB-Fc from 30 to 60 min (but not 70e100 min) after LTP induction (Kang et al., 1997). In general, acute pharmacological inhibition of BDNFTrkB in the CA1 region produces the same slowly decaying LTP that is observed in the presence of PSIs (Table 1). However, it is not known whether BDNF acts through regulation of protein synthesis to stabilize these forms of LTP. In the case of HFS-LTP in CA1, it is notable that treatment with proteins synthesis inhibitors at 35 min post-HFS, a time when TrkB-Fc is effective, fails to inhibit LTP maintenance (Frey and Morris, 1997; Cammalleri et al., 2003). Tanaka et al. (2008) demonstrated a role for endogenous BDNFTrkB signaling in protein synthesis-dependent structural plasticity at single spines in organotypic hippocampal slice cultures. LTP was induced by pairing two-photon uncaging of glutamate at a single spine with generation of postsynaptic action potentials in the postsynaptic neuron. This pairing protocol generated a rapid and persistent spine enlargement, but only the slowly developing late phase of spine enlargement was inhibited by anisomycin and TrkBFc. Glutamate pulses applied in the absence of postsynaptic spikes produced only transient spine enlargement, whereas glutamate pulses combined with exogenous BDNF generated persistent, protein synthesis-dependent enlargement of spines. Importantly, spine enlargement induced by glutamate/spike pairing was blocked by anisomycin even in the presence of BDNF. These data suggests 1) that endogenous BDNF-TrkB promotes stable spine enlargement through a protein synthesis-dependent mechanism, 2) that the source of secreted BDNF, triggered by postsynaptic spiking, is probably postsynaptic. The effects of exogenous BDNF have also shed light on BDNF function and mechanisms in synaptic plasticity (Table 1). Brief perfusion of BDNF has been show to induce LTP (BDNF-LTP) in the medial perforant path input to dentate gyrus (Messaoudi et al., 1998, 2007; Ying et al., 2002), the mossy fiber input to CA3 (Gómez-Palacio-Schjetnan and Escobar, 2008), the Schaffer collateral input to CA1 (Kang and Schuman, 1995; Alarcon et al., 2004; Diogenes et al., 2007; Tebano et al., 2008; Ji et al., 2010), the basolateral amygdala input to insular cortex (Escobar et al., 2003), the lateral geniculate nucleus input to visual cortex (Jiang et al., 2001), and the C-fiber input to the spinal cord dorsal horn (Zhou et al., 2008). A requirement for protein synthesis in BDNF-LTP and occlusion with L-LTP has so far been shown in the CA1 region, dentate gyrus, and spinal cord. BDNF-LTP is also protein synthesis-dependent when the CA1 synaptic neuropil is excised from the cell body layers, showing that this LTP requires local mRNA translation and can be generated independently of cell bodyderived mRNA and protein (Kang and Schuman, 1996). This contrasts with the situation in the DG, where BDNF-LTP induction is suppressed by the transcription inhibitor actinomycin D (Messaoudi et al., 2002). BDNF induces somatodendritic expression of Arc mRNA in dentate granule cells, and Arc protein synthesis is required for the induction and stabilization of BDNF-LTP (Messaoudi et al., 2007). While the relative contribution of somatic versus dendritic synthesis in these brains regions remains to be systemically compared, it can be concluded that BDNF-LTP requires transcription in DG, but not CA1.

Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

CA1 hippocampus

Transcriptiondependent Protein synthesisdependent

BDNF-TrkB critical period ERK-dependent

mTORC1-dependent

Arc-dependent

Reversed by ZIP

Dentate gyrus

HFS-LTP

TBS-LTP

STDP

BDNF-LTP

BDNF rescue

HFS-LTP

BDNF-LTP

Yes (Frey et al., 1996) (Nguyen et al., 1994) Yes (Frey et al., 1988; Kelleher et al., 2004; Stanton and Sarvey, 1984) 30e60 min (Kang et al., 1997) Yes (English and Sweatt, 1997; Kelleher et al., 2004)

No (Huang and Kandel, 2005) Yes-local (Pang et al., 2004; Huang and Kandel, 2005)

n.d

No (Pang et al., 2004)

Yes (Frey et al., 1996)

Yes (Messaoudi et al., 2002)

Yes (Tanaka et al., 2008)

No (Kang and Schuman, 1996) Yes-local (Kang and Schuman, 1996)

No (Pang et al., 2004)

Yes (Krug et al., 1984; Otani et al., 1989)

Yes (Messaoudi et al., 2007)

n.d

n.d.

n.d

n.d.

n.d.

Yes (Watanabe et al., 2002)

n.d

n.d

Yes (Ying et al., 2002; Kanhema et al., 2006)

n.d

Yes (Tang et al., 2002)

n.d

Yes (Davis et al., 2000; Rosenblum et al., 2002; Panja et al., 2009) No (Panja et al., 2009)

n.d.

n.d.

n.d

n.d

n.d.

Yes (Mei et al., 2011)

10 min (Ji et al., 2010) Yes (Patterson et al., 2001; Selcher et al., 2003)

Yes (Tang et al., 2002; Cammalleri et al., 2003) Yes (Plath et al., 2006)

Yes (Alarcon et al., 2004; Huang and Kandel, 2005) n.d.

Yes (Ling et al., 2002; Pastalkova et al., 2006)

Yes (Mei et al., 2011)

Yes (Guzowski et al., 2000; Messaoudi et al., 2007; Plath et al., 2006 (TBS) Yes (Pastalkova et al., 2006)

n.d.

Yes (Messaoudi et al., 2007)

n.d.

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Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

Table 1 Properties of L-LTP forms in the CA1 region and dentate gyrus.

HFS-LTP (High-frequency stimulation-induced LTP): The most common HFS paradigm used in the CA1 region of hippocampal slices is 100 Hz stimulation for 0.5e1 s. 100 Hz HFS applied in multiple sessions induces transcription-dependent L-LTP. In the dentate gyrus of live rats, HFS typically consists of 400 Hz trains of short-duration (8-pulses). Theta-burst stimulation-induced LTP (TBS-LTP): TBS consists of 10 or more 100-Hz bursts, delivered at the frequency (5 Hz) of the theta rhythm. STDP (Spike-Timing-Dependent Plasticity): Glutamate uncaging at a single spine is paired with action potentials generated by somatic depolarization. BDNF-LTP: Long-lasting enhancement in fEPSPs induced by exogenous BDNF. BDNF rescue: Exogenous BDNF enables induction of TBS-LTP in the presence of protein synthesis inhibitors. ZIP (zeta inhibitory peptide): myristoylated 13 amino acid pseudosubstrate inhibitor of protein kinase Mz. n.d.: not determined.

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2.2. Exogenous BDNF and local translation BDNF treatment of cortical and hippocampal synaptoneurosomes (biochemical fractions enriched in pinched-off glutamatergic terminals and connected dendritic spines) induces enhanced synthesis of a wide range of postsynaptic proteins many of which are also synthesized during LTP (GluA1, Arc, aCaMKII, PSD95, etc). Evidence for enhanced synthesis in synaptoneurosomes is based on mRNA abundance in polysomes fractions and S35methionine incorporation into protein (Yin et al., 2002; Schratt et al., 2004; Liao et al., 2007). In one study, BDNF enhanced the expression of several hundred proteins in synaptoneurosomes from cortical cultures (Liao et al., 2007). In addition, BDNF has also been found to regulate expression of translation factors and RNA-binding proteins involved in RNA transport and translation (Schratt et al., 2004; Liao et al., 2007; Manadas et al., 2009; Santos et al., 2010; Leal et al., 2013). Time-lapse imaging studies in primary hippocampal neuronal cultures show that microperfusion of BDNF across a dendritic segment induces translation of a myristoylated GFP reporter flanked by the 50 and 30 -UTR of aCaMKII (Aakalu et al., 2001). In neurons cultured in microfluidic chambers, BDNF induces local synthesis of YFP-tagged PSD-95 in isolated dendrites (Butko et al., 2012). Electron microscopic studies further showed that newly synthesized PSD-95, tagged with the singlet oxygen generator (miniSOG), localizes to the PSD. Dieterich et al. (2010) demonstrated BDNF enhancement of somatic and dendritic protein synthesis using a novel, non-radioactive metabolic labeling method. After pulse-labeling with a non-canonical methionine surrogate, azidohomoalanine (AHA), the newly synthesized proteins are chemically conjugated (“clicked”) to a fluorescent alkyne tag for in situ visualization. When chemically conjugated to an alkynebearing biotinylated probe, newly synthesized proteins can be affinity-purified for identification by mass spectroscopy (Hodas et al., 2012). Recently, the latter method was combined with stable-isotope labeling of amino acids in cell culture (SILAC) to quantify changes in the proteome of activated T cells (Howden et al., 2013). This click-SILAC approach represents a particularly powerful tool for identifying and quantifying rapid changes in protein synthesis elicited by exogenous and endogenous BDNF. 2.3. BDNF and translational control Translation initiation is the process whereby the ribosome is recruited to the mRNA and scans to the start codon (Kong and Lasko, 2012). A major control point in this process is the assembly of the eukaryotic initiation factor 4F (eIF4F) complex on the 50 terminal m7GpppN cap structure. The three core components of eIF4F are the cap-binding protein eIF4E, which recruits the scaffolding protein, eIF4G, and the RNA helicase, eIF4A. Translation is repressed by eIF4E-binding proteins (4E-BPs), which in their unphosphorylated state effectively sequester eIF4E to block the eIF4E-eIF4G interaction. Phosphorylation of 4E-BP catalyzed by the mammalian target of rapamycin complex 1 (mTORC1) triggers the release of 4E-BP, resulting in eIF4F formation and enhanced rates of translation (Gingras et al., 2001; Proud, 2007). Combined evidence from numerous studies employing pharmacological and genetic manipulation of the mTORC1 pathway support a role for mTORC1 signaling to 4E-BP in the regulation of protein synthesis critical to LTP and LTD and long-term memory (Stoica et al., 2011; Gkogkas et al., 2013; Santini et al., 2013). Another important mTORC1 substrate for translation is p70 S6 kinase (S6K1 and S6K2). S6K phosphorylates a number of proteins with roles in translation, including ribosomal protein S6, eIF4B, elongation factor 2 kinase, and fragile X mental retardation protein (FMRP). Although S6K activation is

observed after LTP induction, LTP maintenance appears to be normal in S6K1 and S6K2 knockout mice (Antion et al., 2008). ERK signaling to MAP-kinase interacting kinases (MNKs) is considered to enhance translation rates, and is usually considered to work in parallel with mTORC1. MNKs bind directly to eIF4G and catalyze the phosphorylation of eIF4E at Ser209, resulting in decreased affinity of eIF4E for the cap structure (Scheper et al., 2002; Waskiewicz et al., 2007; Buxade et al., 2008). While ERKMNK signaling contributes to LTP maintenance and translation (Panja et al., 2009; Gal-Ben-Ari et al., 2012), the function of eIF4E phosphorylation for mRNA translation is largely unknown. An overview of the TrkB receptor pathways coupling to translation is shown in Fig. 1. Exogenous BDNF activates the ERK-MNKeIF4E pathway and mTORC1 signaling to both 4E-BP and S6K in dendrites of cultured neurons (Takei et al., 2001). BDNF application triggers protein synthesis in synaptoneurosomes as well as dendrites of cultured neurons through mTORC1 activation (Takei et al., 2004). Schratt et al. (2004) demonstrated PI3K/mTORC1dependent polysome formation in hippocampal neuronal cultures and show that many synaptic proteins and proteins involved in ribosome assembly and translation control are synthesized in a rapamycin-sensitive manner. Recent work on a mouse model of Down syndrome sheds light on endogenous BDNF-TrkB regulation of translation in dendrites. Ts1Cje mice are trisomic for the Down syndrome critical region (DSCR) that is considered necessary for intellectual disability in the humans. Ts1Cje mice exhibit constitutively elevated expression of proBDNF and mature BDNF in the hippocampus (TrocaMarín et al., 2011). These mice also exhibit increased basal activation of the PI3K-Akt-mTORC1 pathway to 4E-BP and S6K in dendrites of hippocampal neurons and increased rapamycinsensitive protein synthesis in synaptoneurosomes. This state of chronic hypertranslation occludes activation of PI3K-mTORC1 by exogenous BDNF and is blocked by TrkB-Fc. In contrast, TrkB signaling to Ras-ERK and downstream phosphorylation of MNK and eIF4E was not enhanced in neurons from Ts1Cje mice relative to wildtype, and could be activated normally by BDNF treatment. The Ts1Cje mice also have enhanced glutamatergic activity, suggesting a complex response with effects on translation. Nonetheless, the data implicate mTORC1, rather than ERK, in BDNF activation of dendritic translation in CA1 pyramidal cells. The basis for the selective coupling of TrkB to mTORC1 is currently unknown but could be related to trisomic expression of >80 genes in Ts1Cje mice. DSCR1, one of the proteins trisomic in Down syndrome, binds to and inhibits the calcium-dependent phosphatase, calcineurin (Fuentes et al., 2000). DSCR1 knockout mice are known to have impaired L-LTP and memory (Hoeffer et al., 2007). Recently, DSCR1 was identified as an important regulator of BDNF-induced dendritic translation and spine morphogenesis (Roselli, 2012; Wang et al., 2012). To visualize new protein synthesis in dendrites, Wang and colleagues transfected hippocampal neurons with the photoconvertible fluorescent protein Dendra2 flanked by 50 - and 30 -UTRs of aCaMKII. BDNF-induced translation of the reporter was inhibited in neurons from DSCR1-/- knockout mice and enhanced in DSCR1 transgenic mice. Mechanistically, Wang and colleagues show that DSCR1 regulates the phosphorylation state of the RNA-binding protein FMRP. When phosphorylated on Ser500, FMRP represses translation of its target mRNAs (possibly through regulation of the translation elongation step). DSCR1 binds phosphorylated FMRP and serves to maintain the phosphorylated state by inhibiting calcineurin phosphatase activity. Upon BDNF treatment, phosphorylation of DSCR1 triggers activation of calcineurin, resulting in dephosphorylation of FMRP, release of the DSCR1/calcineurin complex from FMRP, and enhanced synaptic translation. The BDNF

Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

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Fig. 1. TrkB receptor coupling to translational control and actin cytoskeletal dynamics in dendritic spines. This illustration depicts the majority of the signaling pathways and mechanisms discussed in this review of relevance for functional and structural plasticity in L-LTP. The summary is based on data obtained in different brain regions, experimental preparations, and paradigms. Many of the downstream pathways have not yet been shown to be regulated by endogenous BDNF in the context of L-LTP. Current evidence suggests that TrkB regulates multiple forms of mRNA-specific translation, controlled by CYFIP1, FMRP, and microRNAs, as well as more general regulation of translation initiation through mTORC1 and MNK. Dual regulation of translation and cytoskeletal dynamics by BDNF is another emerging theme. Reciprocal mechanisms may exist whereby cytoskeletal regulation promotes local translation, and translated proteins (such as Arc and LIMK1) influence actin filament assembly and stabilization. There is also extensive cross-talk between the RasERK, PI3K-mTORC1, and PLCg1 pathways.

evoked signaling pathways leading to phosphorylation of DSCR1 are yet to be identified. In a new twist on mTOR regulation, recent evidence suggests that activation of the calcium-dependent cysteine protease, calpain, facilitates coupling of TrkB to mTORC1 and dendritic protein synthesis (Briz et al., 2013). In rat hippocampal slices, cortical synaptoneurosomes, and cultured cortical neurons, BDNF-induced mTORC1 activation and protein translation were blocked by a calpain inhibitor (calpain inhibitor III). TrkB-ERK dependent phosphorylation and activation of calpain-2 promoted proteolysis of PTEN (phosphatase and tensin homolog deleted on chromosome 10), a phosphatase that inhibits Akt activity and signaling to mTORC1. Through an unknown but calpain-dependent mechanism, BDNF also stimulated degradation of tuberous sclerosis complex

proteins (TSC1 and TSC2), both of which are negative regulators of mTORC1. In addition to the 4E-BP isoforms, several non-canonical 4E-BPs have been identified in neurons, including maskin, CYFIP1, and neuroguidin (Napoli et al., 2008; Udagawa et al., 2012). Through dual interaction with eIF4E and an RNA-binding protein, these noncanonical 4E-BPs regulate formation of the translation initiation complex in an mRNA-specific manner. Cytoplasmic FMRPinteracting protein 1 (CYFIP1) is of particular interest with regard to BDNF regulation of translation. In hippocampal neuronal cultures or cortical synaptoneurosomes, exogenous BDNF triggers the release of CYFIP1 from eIF4E on the mRNA cap to facilitate synthesis of several well-established FMRP target mRNAs, including Arc, Map1B, and aCaMKII (Napoli et al., 2008). However, the signal

Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

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transduction pathways and molecular mechanisms controlling CYFIP1 binding to eIF4E are currently unknown. BDNF has been shown to modulate local protein synthesis and spine morphology through regulation of miRNA biogenesis and modulation of the miRNA-induced silencing complex (Vo et al., 2010; Siegel et al., 2011). Recent work gives novel insights into BDNF regulation of translation through the coordinate modulation of pre-miRNA processing (Huang et al., 2012; Ruiz et al., 2013). BDNF induces rapid expression of the miRNA processing enzyme, Dicer, and stabilization of its activity through phosphorylation of the Dicer binding partner TRBP (Huang et al., 2012). Dicer expression results in enhanced processing of pre-miRNA to mature miRNA and formation of processing bodies (P-bodies) in dendrites. In parallel with Dicer expression, BDNF enhances expression of the RNA-binding protein, Lin28a. Lin28 recognizes a “GGAG” sequence motif in the terminal loop region of Let-7 family miRNAs (and also in miR-107 and miR-143) and functions to selectively block Dicermediated processing of these pre-miRNAs. Through this dual mode of regulation, BDNF enhances the global production of miRNAs, while specifically depleting neurons of Lin28a-targeted miRNAs. Functionally, this miRNA-mediated mechanism confers specificity to BDNF effects, allowing enhanced dendritic translation of a panel of Lin28a-targeted mRNAs (e.g GluA1, aCaMKII, and homer2). 2.4. Translational control of Arc synthesis-dependent LTP In sum, it seems clear that endogenous BDNF signaling can promote L-LTP through a protein synthesis-dependent mechanism, that exogenous application of BDNF can generate protein synthesisdependent LTP, and that BDNF signaling regulates the activity of the translation machinery in dendrites. However, the set of proteins that are regulated by endogenous BDNF and whose synthesis is required to mediate L-LTP have yet to be identified. Most studies linking specific proteins to late phase LTP have employed gene knockout and overexpression. While immensely informative, the impact of gene deletion or inducible gene knockdown does not necessarily reflect the function of newly synthesized protein. One protein that is synthesized in response to BDNF signaling and required for L-LTP formation is activity-regulated cytoskeleton associated protein (Arc; also termed Arg3.1). Arc is rapidly induced as an immediate early gene whereupon a fraction of the new RNA is transported to dendrites for local storage, translation, or decay. Arc protein synthesis is required for stabilization of long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity, and for postnatal development of the visual cortex and consolidation of long-term memory (Bramham et al., 2010; Korb and Finkbeiner, 2011; Shepherd and Bear, 2011). In the dentate gyrus, inhibition of Arc expression by antisense oligodeoxynucleotides (AS-ODN) inhibits LTP maintenance (Guzowski et al., 2000; Messaoudi et al., 2007). Messaoudi et al. (2007) used acute AS-ODN infusion to assess the dynamic contribution of new Arc synthesis to LTP maintenance. LTP is transiently inhibited by Arc AS-ODN infusion at 5 min post-HFS, rapidly and permanently inhibited by AS-ODN infusion at 2 h post-HFS, but unaffected by Arc AS-ODN at 4 h post-HFS. The rapid reversion of LTP (within 30 min of AS-ODN infusion) was matched by inhibition of Arc protein expression as assessed by immunohistochemical staining and western blot analysis of dentate gyrus lysates. In addition, BDNF-LTP induced by acute, local infusion of BDNF is abolished by Arc AS-ODN and occluded by prior induction of L-LTP, but not early LTP (Messaoudi et al., 2002, 2007). Arc synthesis is also required for consolidation of BDNF-LTP over the same time period as observed for HFS-LTP. This suggests that exogenous BDNF is capable of activating Arc-dependent L-LTP. As discussed in

section 4.1, Arc synthesis is required for stable increases in F-actin in HFS-LTP of the dentate gyrus. Arc translation-dependent LTP in the DG is associated with novel translational control (Panja et al., 2009). In contrast with studies of LTP in the CA1 region (Tang et al., 2002; Stoica et al., 2011), rapamycin treatment does not impair LTP maintenance in the DG. HFS of the medial perforant pathway triggers robust activation of mTORC1 (S2448 phosphorylation) and downstream signaling to S6K and phosphorylation of ribosomal protein S6. However, rapamycin treatment blocks mTORC1-S6K-rpS6 signaling without affecting LTP maintenance during 10 h of recording. Rapamycin also fails to inhibit the increase in eIF4F formation and Arc protein synthesis during LTP (Panja et al., 2009). Moreover, mTORC1 catalyzed phosphorylation of 4E-BP2 and release of 4E-BP2 from eIF4E, which is known to occur in CA1 LTP (Banko et al., 2005; Gelinas et al., 2007), is not detected in cap-pulldown assays performed in DG lysates. In contrast, pharmacological inhibition of MEK (with U0126) or MNK (with CGP57380) effectively blocks HFS-induced eIF4F formation, eIF4E phosphorylation, and Arc protein expression while inhibiting formation of L-LTP in the DG. The work therefore supports a dominant role for MNK, rather than mTORC1, in stabilization of medial perforant path-DG LTP. Exactly how MNK gates eIF4F formation is one of the pressing issues arising from this work. Given evidence that 4E-BP2 remains bound to eIF4E during LTP maintenance, it is possible that MNK triggers release of a non-canonical eIF4E binding protein to facilitate eIF4E-eIF4G interactions. CYFIP1 is a promising candidate for this role given evidence that BDNF triggers release of CYFIP/FMRP from the eIF4E and promotes Arc translation in hippocampal neurons (Napoli et al., 2008). 3. BDNF and protein synthesis-independent LTP stabilization TBS-LTP in region CA1 of hippocampal slices is considered to be a local form of LTP requiring BDNF signaling and dendritic translation, but not somatic transcription (Huang and Kandel, 2005; Sajikumar and Korte, 2011). Several studies demonstrate that inhibition of late TBS-LTP by PSIs is overcome by perfusing slice with BDNF (Pang et al., 2004; Santi et al., 2006). In this paradigm, stable TBS-LTP is rescued when BDNF is applied no later than 15 min postTBS. Santi et al. (2006) further provided evidence that exogenous BDNF is endocytosed and later released in response to TBS. BDNF expression in CA1 pyramidal cell bodies was increased in slices incubated in BDNF for 60 min prior to transferring the slices to a recording chamber lacking BDNF medium. In BDNF pre-treated slices, TBS-LTP was induced in the presence of anisomycin and this rescue effect was blocked by applying TrkB-Fc from 5 min before to 15 min post-TBS. The authors therefore suggest that endocytosed mature BDNF is fed back to an activity-dependent releasable pool required for LTP maintenance. The rat BDNF gene expresses 22 transcripts containing 11 different 50 -UTRs, a common coding region, and either a long or short 30 -UTR (Timmusk et al., 1993). These distinct UTRs confer differential subcellular localization and translation of BDNF transcripts (An et al., 2008; Baj et al., 2011). BDNF mRNA bearing the long 30 -UTR has a broad somatodendritic distribution. Truncation of the long 30 -UTR abolishes dendritic expression but retains somatic expression of BDNF mRNA. Interestingly, mice expressing a 30 -UTR truncated form of BDNF mRNA show impaired dendritic expression of BDNF protein, blunted developmental pruning of dendritic spines in layer 2/3 pyramidal neurons of the visual cortex, and impaired ocular dominance plasticity (An et al., 2008; Kaneko et al., 2012). Moreover, L-LTP is impaired at synaptic inputs onto CA1 pyramidal cells dendrites but not inputs onto cell bodies (An et al., 2008). These data clearly support a role for dendritic BDNF

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synthesis, and presumably release, in the modulation of dendritic spine structure and function. Taken together, these studies indicate a pivotal role for activityinduced synthesis of BDNF in dendrites in the formation of late phase TBS-LTP in hippocampal region CA1. The rescue experiments further suggest that BDNF acts, at least in part, by protein synthesisindependent mechanisms. 3.1. Mechanism of exogenous BDNF rescue of L-LTP The persistently active protein kinase, protein kinase Mz (PKMz), is the only molecule implicated in perpetuating maintenance of LTP, LTD, and long-term memory (Sacktor, 2011). Persistent PKMz activity is thought to be maintained by persistent synthesis of the enzyme in dendrites. PKMz synthesis is repressed by the peptidyl-prolyl isomerase, Pin1, probably through association of Pin1 with 4E-BP2 and eIF4E. Glutamatergic signaling phosphorylates and inactivates Pin1 to facilitate synthesis of PKMz. PKMz can then act in feedback manner to phosphorylate Pin1 and maintain PKMz synthesis (Kelly et al., 2007; Westmark et al., 2010; Sacktor, 2011). In this model, persistent PKMz activity would enhance excitatory synaptic transmission by decreasing constitutive endocytosis of the GluA2 subunit of AMPA receptors (Sacktor, 2011). In the CA1 region of acute mouse hippocampal slices, TBS-LTP maintenance is inhibited by treatment of slices with zeta inhibitory peptide (ZIP), a myristoylated pseudosubstrate peptide inhibitor of PKMz (Mei et al., 2011; Yao et al., 2013). TBS induces an increase in PKMz expression at 1 h post-TBS that is blocked by anisomycin treatment (Mei et al., 2011). In BDNF rescue experiments, a delayed increase in PKMz expression is observed three hours after TBS in the presence of anisomycin. This protein synthesis-independent potentiation is rapidly reverted by ZIP application to the slice. The authors propose that BDNF signaling enhances PKMz expression by inhibiting its degradation. Endogenous BDNF signaling has been implicated in activity-dependent ubiquitination and enhanced turnover of synaptic proteins in cultured hippocampal neurons (Jia et al., 2008), and L-LTP formation requires ubiquitin proteasome system (UPS)-mediated protein degradation (Bingol and Schuman, 2005; Fonseca et al., 2006; Bingol and Sheng, 2011). However, it is unclear whether BDNFinduced inhibition of protein degradation also occurs, as may be the case for PKMz. BDNF induced trafficking of the scaffolding protein PSD-95 has been identified as a potential mechanism for protein synthesisindependent rescue of L-LTP. PSD-95 is a key determinant of PSD size and synaptic strength in neuronal development, experiencedependent plasticity, as well as LTP/LTD (Migaud et al., 1998; Ehrlich and Malinow, 2004). PSD-95 acts at least in part by regulating the diffusional trapping and anchoring of synaptic AMPA receptors (Opazo et al., 2012). In postnatal development of the visual cortex, eye-opening and the onset of pattern vision increases BDNF-TrkB signaling, maturation of dendritic spines, and promotes visual cortex plasticity (Castren et al., 1992; Yoshii and ConstantinePaton, 2010). In cultured visual cortical neurons, BDNF signaling through PI3K/Akt promotes vesicular transport of PSD-95-GFP to dendrites and accumulation of PSD-95 at synaptic puncta in a protein synthesis-independent manner (Yoshii and ConstantinePaton, 2007, 2010). BDNF-coated microspheres touching one dendrite promotes PSD-95-GFP fluorescence recovery after photobleaching across the entire dendrite, indicating a dendrite-wide mobilization of PSD-95. In a related finding, PSD-95 transport into spines was found to be dependent on BDNF-induced microtubule invasions into spines (Hu et al., 2011). A link has also been established between PKMz activity and PSD-95 translocation to

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synapses (Yoshii et al., 2011). Palmitoylation of PSD-95 is required for attachment of the protein to vesicular membranes and insertion at synapses. TrkB activation regulates the palmitoylation of PSD-95 and vesicular transport of PSD-95 to dendrites of layer 2/3 neurons in developing visual cortex. Both TrkB-PLCg and PKMz are necessary for PSD-95 palmitoylation, and PKMz was found to selectively phosphorylate the palmitoylation enzyme ZDHHC8. Cortical injection of ZIP inhibited expression of PSD-95-GFP in synaptic puncta, while in utero electroporation of ZDHHC8 rescued PSD-95GFP expression in layer 2/3 cortical neurons as measured in cortical slices obtained one day after eye-opening. As detailed by Yoshii and Constantine-Paton (2010), BDNF-induced synaptic recruitment of PSD-95 in cooperation with pathways downstream of NMDAR activation could promote L-LTP during visual cortical plasticity after eye-opening, and these same mechanisms might function in BDNF rescue of L-LTP in the hippocampus. Recently, the PKMz hypothesis and the specificity of ZIP as an inhibitor of PKMz was called into question by reports showing that mice with constitutive or conditional knockout of PKMz have intact LTP and memory, yet ZIP remains an effective inhibitor of LTP in these mice (Lee et al., 2013; Volk et al., 2013). Although ZIP (but not scrambled peptide) was shown to block phosphorylation of PKMz and potentiation of postsynaptic AMPA responses (Yao et al., 2013), it is presently uncertain whether the ability of ZIP to inhibit BDNF rescue and phosphorylation of ZDHHC are due specifically to inhibition of PKMz. Another interesting aspect of BDNF-TrkB synaptic function with relevance to BDNF rescue is synaptic tagging and capture (Lu et al., 2011; Sajikumar and Korte, 2011). The classic experimental paradigm for showing tagging and capture involves two convergent inputs on CA1 pyramidal cells in hippocampal slices (Frey and Morris, 1997). Strong stimulation of input 1 (S1) generates synthesis of plasticity-related proteins (PRPs) which can be captured by subsequent stimulation of a second input (S2) receiving only weak stimulation. Weak stimulation of S2 is said to set a synaptic “tag” that allows the capture of PRPs and conversion of early LTP to L-LTP. Recent work suggests that BDNF is a PRP, while activated TrkB is a synaptic tag for L-LTP and long-term memory (Lu et al., 2011). Earlier work showed that deletion of BDNF in CA1 pyramidal cells abolished the ability of the weak input to undergo L-LTP in the two-pathway experiment (Barco et al., 2005). More recently, Lu et al. (2011) studied synaptic tagging in knock-in mice expressing TrkB receptors sensitive to inhibition by 1NMPP1. The authors found that inhibition of TrkB by bath application of 1NMPP1 from 40 to 60 min after strong (12xTBS) stimulation of S1 blocks the capture of L-LTP at weakly stimulated (4xTBS) S2. Interestingly, inhibition of TrkB at the time of S1 stimulation blocks L-LTP at that input without preventing capture on S2. This suggested that L-LTP on S1 requires a TrkBdependent synaptic tag, or possibly just TrkB activation. On S2, weak stimulation is sufficient to activate TrkB and capture the previously synthesized PRPs that were induced by strong stimulation on S1 and transported to dendrites. Taken together with studies on BDNF rescue of LTP, the data support the model in which BDNF is synthesized in the postsynaptic neuron in response to strong TBS, then released and captured at synapses a by TrkB-dependent mechanism. Given the work of Yoshii et al. (2011), recruitment of PSD-95 to spines could function in LTP expression, or possibly as part of the TrkB-dependent tagging mechanism. It is not clear whether BDNF release is synapse-specific, such that only the synapses tagged by TrkB activation are capable of releasing BDNF and sustaining LTP. Work on hometostatic plasticity in hippocampal neurons provides evidence for presynaptic regulation of glutamatergic transmission mediated by local, postsynaptic synthesis and release of BDNF (Jakawich et al., 2010). Postsynaptic activity blockade (induced by the AMPA glutamate receptors antagonist NBQX)

Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

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increases the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), indicating a presynaptic modification. The increase in mEPSPC frequency was blocked by local application of TrkB-Fc or treatment with the PSIs anisomycin and emetine. shRNA-mediated knockdown of BDNF in postsynaptic neurons failed to block a rapid increase in mEPSC amplitude observed with AMPAR block, but did block the delayed selective increase in mEPSC frequency. Furthermore, increases in mEPSC frequency induced by exogenous BDNF were not blocked by anisomycin. To the extent these mechanisms in developing neurons in culture can be extrapolated to adult synapses, they suggest that postsynaptically synthesized BDNF could mediated protein synthesis-independent potentiation through retrograde effects on glutamate release from presynaptic terminals. 4. BDNF regulation of actin cytoskeletal dynamics Regulation of actin cytoskeletal dynamics in dendritic spines is required for LTP formation and associated enlargement of dendritic spines (Bourne et al., 2007; Bramham, 2008; Murakoshi and Yasuda, 2012). Much has been learned about mechanisms of actin regulation in spines and the diverse functions of spine F-actin and actin-based motor proteins in receptor and membrane trafficking, organelle movement, and remodeling of the PSD (Frost et al., 2010; Penzes and Rafalovich, 2012; Kneussel and Wagner, 2013; Rácz and Weinberg, 2013). For the purpose of this review, we discuss evidence that BDNF signaling regulates spine F-actin in L-LTP, and how regulation of the actin cytoskeletal dynamics relates to local protein synthesis. In CA1 pyramidal cells of acute hippocampal slices, exogenous BDNF triggers inhibition (phosphorylation) of the actin-severing protein cofilin in spines, while application of TrkB-Fc or an Factin destabilizing drug, latrunculin A, inhibits F-actin formation and development of late TBS-LTP (Rex et al., 2007). Importantly, these effects require that TrkB-Fc and latrunculin A are applied within 2 min of TBS. Activation of RhoA kinase (ROCK), upstream of the cofilin kinase, LIMK1, is required for rapidly increasing phospho-cofilin and spine F-actin (Rex et al., 2009). Using the Rac GTPase inhibitor NSC23766, the study provides evidence for a role of Rac signaling to p21-activated protein kinase (PAK) in the consolidation of LTP. Inhibition of Rac-PAK extended the time window over which LTP is sensitive to disruption by latrunculin A from 2 min to approximately 10 min post-TBS. PAK is a known regulator of actin filament branching and cross-linking (Bokoch, 2003; Penzes and Rafalovich, 2012), and mice deficient in PAK3 have impaired late phase LTP (Meng et al., 2005). In sum, this suggests that nascent F-actin generated by the RhoA-ROCK-cofilin pathway is stabilized by Rac-PAK signaling over a period lasting 2e10 min. As late TBS-LTP has an overlapping time-window of sensitivity to TrkB inhibition, it is conceivable that both of these actin regulatory pathways are modulated by TrkB signaling (Fig. 1). It also important to note that regulation of LTP by BDNF is itself modulated by extracellular adenosine levels. Acute activation of adenosine A1 receptors during TBS interferes with Rho-ROCK dependent actin filament assembly in spines (Rex et al., 2009), while tonic activation of adenosine A2A receptors is permissive for BDNF-induced LTP and BDNF facilitation of early TBS-LTP at Schaffer collateral-CA1 synapses (Diogenes et al., 2007; Fontinha et al., 2008; Tebano et al., 2008). These permissive effects of A2A receptor activation are thought to involve cAMP-dependent modulation of BDNF secretion (Tebano et al., 2008). 4.1. Translation/actin cytoskeletal dynamics: reciprocal interactions Interactions between local translation and actin cytoskeletal regulation are important in growth cone turning and spine

morphogenesis, and could also function in L-LTP in the adult brain (Bramham and Wells, 2007; Van Horck and Holt, 2008). TrkB signaling regulates local translation of many mRNAs with key roles in cytoskeletal regulation including RhoA and LIMK1 (Schratt et al., 2006; Troca-Marín et al., 2010). During the window of LTP consolidation in the dentate gyrus, sustained Arc synthesis is necessary for cofilin phosphorylation and stable increases in synaptic F-actin content (Messaoudi et al., 2007). Arc protein expression and enhanced phalloidin staining of F-actin in the medial perforant path termination zone is rapidly inhibited by infusion of Arc AS-ODN at 2 h post-HFS. Local infusion of the F-actin stabilizing drug jasplakinolide after LTP induction, but before AS-ODN infusion, rescues LTP and prevents loss of nascent F-actin. Taken together, this suggests that LTP consolidation requires a period of sustained Arc synthesis during which Arc functions to stabilize nascent F-actin. Exogenous BDNF induces Arc-dependent LTP (Messaoudi et al., 2007), and LTP in the DG is associated with enhanced synaptic TrkB activation and increased depolarizationevoked release of BDNF from synaptosomes (Gooney and Lynch, 2001; Gooney et al., 2004). However, it is not known whether endogenous BDNF signaling regulates Arc expression and F-actin formation during DG LTP. Actin filament assembly regulates the subcellular localization and possibly the activity the protein synthesis machinery. Induction of LTP is associated with rapid increases in the spine content of aCaMKII mRNA and polyribosomes, suggesting that components of the translational machinery are locally transported into spines (Ostroff et al., 2002; Havik et al., 2003; Bourne et al., 2007). In cultured hippocampal neurons, BDNF induces an F-actin-dependent trafficking of eIF4E into dendritic spines (Smart et al., 2003). mRNPs and endoplasmic reticulum are transported into spines via the actin-based motor protein myosin-Va, while myosin Vb transports recycling endosomes into spines (Yoshimura et al., 2006; Kneussel and Wagner, 2013). In the dentate gyrus in vivo, local Factin formation is necessary for the selective localization of dendritic Arc mRNA to activated synapses of the medial perforant path (Huang et al., 2007). There is also evidence that actin cytoskeletal remodeling during LTP serves as a tag for the input-specific capture of PRPs (Fonseca, 2012). In the fly midline axon guidance system, F-actin recruits a protein complex including the translation initiation factor eIF2Bε to modulate local translation underlying growth cone turning (Lee et al., 2007; Van Horck and Holt, 2008). The Drosophila protein short stop (Shot) links microtubules to F-actin through direct binding, while the Shot-interacting protein, Krasavietz, binds through its W2 domain to eIF2Bε. Thus, the Shot-Kra-eIF2Bε complex represents a cytoskeletal platform for local translation. It will be important to determine whether actin-binding proteins in spines similarly function in local translation. 4.2. Dual regulation of translation and actin cytoskeletal dynamics In addition to autophosphorylation at tyrosine residues, BDNF can trigger S478 phosphorylation of the juxtamembrane region of TrkB by cyclin-dependent kinase 5 (cdk5) (Cheung et al., 2007) (Fig. 1). In hippocampal neurons from TrkBS478A knock-in mice, BDNF-induced spine morphogenesis and glutamate-induced spine enlargement is impaired (Lai et al., 2012). In the CA1 region of hippocampal slices, late TBS-LTP is impaired, and facilitation of early TBS-LTP by exogenous BDNF is blocked. Cdk5-mediated phosphorylation on TrkB functions to recruit the Rac-specific guanine nucleotide exchange factor, Tiam1. TrkB-coupled Tiam1 then acts in synergy with pathways downstream of NMDA receptors to activate PAK, promote F-actin dynamics, and spine morphogenesis (Fig. 1). Tiam1 regulates actin dynamics through PAK and can also

Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024

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regulate PI3K to exert downstream effects on 4E-BP (Connolly et al., 2005; Tolias et al., 2005). Furthermore, by direct activation of the PI3K-mTOR pathway, Tiam1 activation is necessary for enhanced expression of PSD-95 in response to BDNF. While speculative at the moment, the data suggest that TrkB-Tiam1 signaling to PAK and mTOR might function in regulation of spine actin dynamics and protein synthesis involved in stable LTP and spatial memory. TrkB-dependent activation of calpain may also modulate translation and F-actin dynamics through bifurcating pathways (Fig. 1). As previously discussed, calpain facilitates mTORC1dependent translation through proteolysis of the upstream regulators PTEN and TSC. In addition, BDNF induces actin polymerization in spines of hippocampal neurons through ERK-dependent regulation of calpain 2 (Zadran et al., 2010b). Calpain could act by spectrin cleavage or by truncation of cortactin and other cytoskeletal associated protein (Vanderklish et al., 1995; Perrin et al., 2006; Zadran et al., 2010a). In response to NMDA receptor-dependent calcium influx, calpain also regulates Dicer activity at synapses and is potentially important for microRNA processing and local protein synthesis (Lugli et al., 2005, 2012). Calpain 1 cleaves Dicer from biochemically isolated PSDs and uncovers cryptic RNAase III activity, while active Dicer is generated by NMDA receptor activation in hippocampal slices. Whether BDNF induced calpain activity functions in Dicer regulation is currently unknown, but such a mechanism would fit with BDNF enhancement of Dicer function at hippocampal neuron synapses as shown by Huang et al. (2012). 5. Perspectives and outstanding issues 5.1. Multiple BDNF mechanisms, brain region differences Three general conclusions can be reached. First, BDNF-TrkB can promote L-LTP induction through multiple protein synthesisdependent mechanisms. Second, these mechanisms differ between the CA1 region and dentate gyrus, and probably as a function of the type of LTP induced (TBS or HFS). Third, BDNF synthesized in response to TBS in the CA1 region promotes stable L-LTP through a protein synthesis-independent mechanism. The properties of different forms of L-LTP and BDNF rescue are summarized in Table 1. In the CA1 region of hippocampal slices, BDNF-dependent TBSLTP and exogenous BDNF-LTP both require local (dendritic) protein synthesis but not somatic protein synthesis. HFS-LTP in the Schaffer collateral input to CA1 is transcription-dependent and requires mTORC1 signaling for translation regulation and L-LTP formation. In cultured hippocampal neurons and hippocampal slices, BDNFevoked Arc synthesis is blocked by rapamycin (Takei et al., 2004; Jourdi et al., 2009; Briz et al., 2013). Under conditions that produce BDNF-LTP, however, Arc protein was not induced in the hippocampus (Ji et al., 2010). In contrast, HFS-LTP in the DG of urethane-anesthetized rats is associated with ERK-MNK (not mTORC1) dependent translation initiation and enhanced Arc synthesis over a protracted time-window. Transcription and ERKdependent Arc synthesis is also required for BDNF-LTP in the DG (Messaoudi et al., 2002, 2007; Ying et al., 2002; Kanhema et al., 2006; Wibrand et al., 2006). While differences seem clear, systematic comparisons of BDNF mechanisms in the CA1 and dentate gyrus in the same preparation are needed. Currently, the dynamics of BDNF-TrkB signaling and its impact on downstream signaling events during different forms of LTP are little understood. TBS-LTP in the CA1 region is inhibited by TrkB-Fc applied within 10 min of TBS, while HFS-LTP remains sensitive to TrkB-Fc for 30e70 min after LTP induction. Is the duration of the TrkB phosphorylation determined by BDNF release at the time of LTP induction (Aicardi et al., 2004), or is it sustained by a

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regenerative activation of TrkB? Recent studies in hippocampal neurons and HEK293 cells show that endocytosed full-length TrkB can rapidly recycle to the membrane to promote sustained ERK signaling (Chen et al., 2005; Nagappan and Lu, 2005; Huang et al., 2009, 2013). TrkB activation is known to stimulate BDNF release, and internalized BDNF can be recycled for neuronal activitydependent secretion (Canossa et al., 1997; Santi et al., 2006). In neuronal development, self-amplifying autocrine actions of BDNFTrkB ensure axonal differentiation and growth (Cheng et al., 2011). Such a regenerative mechanism of local BDNF secretion and TrkB recycling could potentially generate a period of sustained TrkB activation in LTP. The fact that TBS-LTP and BDNF-LTP in the CA1 region can be generated in the absence of new transcription does not mean transcription has no place in these forms of plasticity. Somaderived mRNA and protein could serve to stabilize LTP on a delayed time course that extends beyond the recordings done in acute hippocampal slices (Frey et al., 1989). Studies in behaving rats have shown delayed increases and even multiple peaks of mRNA expression occurring long after the first critical period of protein synthesis. In learning studies delayed protein synthesis is necessary for consolidation of LTM (Bekinschtein et al., 2013). The rescue experiments implicate BDNF-induced trafficking of PSD-95 to spines and PKMz activity in protein synthesisindependent potentiation. PSD-95 trafficking involves BDNFinduced microtubule incursions into spines, vesicular transport through a PI3K-dependent mechanism, and palmitoylation of PSD95, possibly through PKMz-mediated phosphorylation of ZDHHC8. Several questions remain. First, is rescued LTP mechanistically identical to L-LTP, a subcomponent of the mechanism, or a stage in development of L-LTP? It is also reasonable to ask how protein synthesis-independent mechanisms interface with TrkB-mediated protein translation. Even in the case of mRNA-specific forms of translation (FMRP targets, let7-miR targets) numerous proteins are expected to be regulated. Conceivably, these newly synthesized proteins are necessary for stabilization of LTP on a time course of days, but are not required for the expression of LTP within the 6e 8 h lifetime of the acute hippocampal slice. In this case, BDNF rescue would represent an intermediate phase of L-LTP expression. This mechanism is also compatible with TrkB/PSD-95 as a synaptic tag for the capture of PRPs. So far it is unknown whether rescued L-LTP lasts as long as conventional TBS-LTP and whether BDNF application is capable of rescuing other forms of protein synthesisdependent LTP and in other brain regions. Finally, there is no universal requirement for BDNF signaling or protein synthesis for LTP measured on the order of hours. It has long been known from work in BDNF knockout mice that not all forms of L-LTP strictly depend on BDNF (Patterson et al., 2001). Abbas et al. (2009) also found that anisomycin and emetine failed to inhibit stable TBS-LTP and HFS-LTP in hippocampal slices from 12 to 20 day-old rats. In the medial perforant path input to DG, a form of L-LTP can occur without ERK activation or induction of Arc (Steward et al., 2007). All of the above studies underscore the need for investigations of synaptic plasticity on the full-time scale of the phenomenon (days-weeks) as studied in behaving animals or possibly in organotypic slice cultures. 5.2. Pathway cross-talk and signal bias In pioneering studies on TrkB-coupling signaling in synaptic plasticity, Minichiello generated knock-in mice carrying a point mutation in either the Shc or PLCg1 docking sites on TrkB. They find that TrkB-PLC, not TrkB-Shc, is necessary for LTP maintenance in CA1 (Minichiello et al., 1999). The lack of impairment in L-LTP in the TrkB-Shc mutant is surprising given that mTOR and

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ERK are downstream of Shc. As previously discussed (Ernfors and Bramham, 2003; Minichiello, 2009), downstream signaling pathways that normally mediate crosstalk from PLC to the Shc may be hyperactivated as part of a compensatory response in TrkB-Shc mutants. PLCg1 association with Grb2-associated binding protein 1 (GAB1) and calcium-dependent activation of calpain are both potential sources of cross-talk to ERK/mTOR signaling, but mechanisms have not been established (see Fig. 1). Extending this line of reasoning, it is possible that TrkB-Shc mutants express a form of LTP mechanistically distinct from that of wildtype mice. TrkB signaling bias as a function of cellular context is another emerging theme. As discussed earlier, constitutive activation of TrkB in Ts1Cje mice leads to selectively enhanced signaling through PI3K-mTORC1 without impact on TrkB coupling to ERK-MNK (Troca-Marín et al., 2011). This extreme signaling bias arising from trisomic expression in the Down syndrome critical region is thus far unexplained at the molecular level. Another exciting recent study gives insight to a specific form of TrkB regulation involving a novel coupling between Arc and PSD-95 (Cao et al., 2013). The authors sought to elucidate mechanisms in Angelman syndrome (AS), an intellectual disability caused by failure to inherit a maternal copy of the ubiquitin protein ligase UBE3A gene. Previous work showed that Arc protein is ubiquitinated by Ube3a and targeted for rapid degradation in the proteasome (Rao et al., 2006; Greer et al., 2010; Soulé et al., 2012). In AS model mice deficient in Ube3a, Arc expression is constitutively exaggerated (Greer et al., 2010). Cao et al. now demonstrate that BDNF induces recruitment of PSD-95 to TrkB. This recruitment is impaired in AS mice and rescued either by shRNA-mediated Arc knockdown or by application of a bridged cyclic peptide that uniquely binds with high affinity to the PDZ1 (postsynaptic density-95/Discs large/zona occludens-1) domain of PSD-95 and blocks its interaction with Arc. This cyclic peptide inhibitor completely restores LTP in the CA1 region from hippocampal slices in AS mice and lowers the threshold for LTP induction in wildtype slices. Importantly, coupling of PSD-95 with TrkB is required for full activation of the PLCg-CaMKII and PI3K-Akt pathways, but is dispensable for TrkB-ERK signaling. In this mechanism, Arc selectively gates TrkB pathways through sequestration of PSD-95. Under conditions of enhanced Arc expression, TrkB signaling to PI3K and PLCg1 is blunted in favor of Ras-ERK. It will be important to determine if TrkB signal bias as demonstrated in these studies plays a role in L-LTP and contributes to regional differences in L-LTP mechanisms. 5.3. BDNF and the protein synthesis playbook Effects of exogenous BDNF on dendritic protein synthesis and modulation of translation control pathways are well-documented. Nonetheless, the roles of endogenous BDNF-TrkB signaling in the translation control of L-LTP are little understood. Does BDNF-TrkB signaling drive protein translation, thereby shaping the consolidation process actively and dynamically? At present, the logic of translation in synaptic plasticity is largely unknown. As BDNF is capable of regulating multiple mRNA-specific and more general forms of translation (Fig. 1), it will be vital to elucidate how these mechanisms may be differentially employed in different forms of L-LTP and cell types. For example, while there are striking differences between the CA1 and DG regions in the use of mTORC1- and ERK-dependent translation in LTP, one has yet to identify the proteins synthesized, the spatial-temporal patterns of their synthesis, and how they contribute to processes like PSD expansion, cytoskeletatal regulation, synaptic tagging, and translational capacity. Conceivably, neuron type-specific translational programs exist for L-LTP.

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Please cite this article in press as: Panja, D., Bramham, C.R., BDNF mechanisms in late LTP formation: A synthesis and breakdown, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.06.024