Dual regulation of translation initiation and peptide chain elongation during BDNF‐induced LTP <i>in vivo</i>: evidence for compartment‐specific translation control

Kanhema, Tambudzai; Dagestad, Grethe; Panja, Debabrata; Tiron, Adrian; Messaoudi, Elhoucine; Håvik, Bjarte; Ying, Shui‐Wang; Nairn, Angus C.; Sonenberg, Nahum; Bramham, Clive R.

doi:10.1111/j.1471-4159.2006.04158.x

Cited by 90 publications

(94 citation statements)

References 52 publications

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“…This was later supported by results showing effects of BDNF on the translation machinery in dendrites of cultures cerebrocortical neurons (Takei et al, 2004) as well as in synaptoneurosome preparations (Kanhema et al, 2006;Takei et al, 2004). The effect of BDNF on the synaptic proteome was analyzed in more detail in synaptoneurosomes isolated from cultured cortical neurons, using multidimensional protein identification technology (MudPIT) and relative quantification by spectra counting.…”

Section: Bdnf-induced Changes In the Neuronal Proteomementioning

confidence: 88%

“…A BDNF-induced increase in the phosphorylation of eIF4E, which is correlated with enhanced rates of translation (Gingras et al, 2004), was also observed in dentate gyrus (DG) following infusion of BDNF to induce LTP (BDNF-LTP) and in DG synaptoneurosomes stimulated with BDNF (Kanhema et al, 2006). Furthermore, BDNF infusion into the DG of anesthetized animals was found to increase eIF4E total protein levels, further suggesting that eIF4E upregulation induces local protein synthesis at the synapse, and may contribute to the effects of BDNF in synaptic potentiation.…”

Section: Bdnf and Regulation Of Translation Machinerymentioning

confidence: 94%

“…eEF2, a GTP-binding protein required for the second step of elongation (ribosomal translation), is also regulated by BDNF, although contrasting results were obtained in different preparations. Local infusion of BDNF was shown to induce a rapid and transient increase in eEF2 phosphorylation in the hippocampal dentate gyrus, under conditions that induce LTP (BDNF-LTP) (Kanhema et al, 2006). This alteration in eEF2 phosphorylation at Thr56 is typically associated with a reduction in the interaction of the elongation factor with ribosomes, thereby decreasing global protein synthesis (Nairn and Palfrey, 1987;Ryazanov et al, 1991Ryazanov et al, , 1988, but an increase in the translation of some dendritic mRNAs (e.g.…”

Section: Bdnf and Regulation Of Translation Machinerymentioning

confidence: 99%

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BDNF-induced local protein synthesis and synaptic plasticity

2014

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a b s t r a c tBrain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and longterm potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-g (PLC-g) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre-and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short-and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

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Section: Bdnf-induced Changes In the Neuronal Proteomementioning

confidence: 88%

Section: Bdnf and Regulation Of Translation Machinerymentioning

confidence: 94%

Section: Bdnf and Regulation Of Translation Machinerymentioning

confidence: 99%

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BDNF-induced local protein synthesis and synaptic plasticity

2014

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“…MEK inhibitors such as U0126 block ERK phosphorylation and attenuate early and late phase LTP in the CA1 region and dentate gyrus (7,25,28,33,34). Here, we investigated the effects of MEK-ERK signaling on dynamic changes in translation factor activity during in vivo LTP.…”

Section: Erk-dependent Regulation Of Initiation Factor Activity and Ementioning

confidence: 99%

“…Phosphorylation of eEF2 on Thr 56 inhibits eEF2-ribosome binding and arrests peptide chain elongation (21,22). Paradoxically, eEF2 is phosphorylated in protein synthesis-dependent forms of LTP and long term depres-sion (23)(24)(25), yet synthesis of several plasticity-related proteins, including Arc, is maintained.…”

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confidence: 99%

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Panja

Dagytė

Bidinosti

et al. 2009

Journal of Biological Chemistry

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100

114

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Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding protein eukaryotic initiation factor 4E (eIF4E) and dephosphorylation of eIF2␣ on a protracted time course matching the time-window of Arc translation. Local infusion of the ERK inhibitor U0126 inhibited LTP maintenance and Arc protein expression, blocked changes in eIF4E and eIF2␣ phosphorylation state, and prevented initiation complex (eIF4F) formation. Surprisingly, inhibition of the mTOR protein complex 1 (mTORC1) with rapamycin did not impair LTP maintenance or Arc synthesis nor did it inhibit eIF4F formation or phosphorylation of eIF4E. Rapamycin nonetheless blocked mTOR signaling to p70 S6 kinase and ribosomal protein S6 and inhibited synthesis of components of the translational machinery. Using immunohistochemistry and in situ hybridization, we show that Arc protein expression depends on dual, ERK-dependent transcription and translation. Arc translation is selectively blocked by pharmacological inhibition of mitogen-activated protein kinase-interacting kinase (MNK), the kinase coupling ERK to eIF4E phosphorylation. Furthermore, MNK signaling was required for eIF4F formation. These results support a dominant role for ERK-MNK signaling in control of translational initiation and Arc synthesis during LTP consolidation in the dentate gyrus. In contrast, mTORC1 signaling is activated but nonessential for Arc synthesis and LTP. The work, thus, identifies translational control mechanisms uniquely tuned to Arc-dependent LTP consolidation in live rats.The adult mammalian brain is known to express diverse forms of activity-dependent synaptic plasticity (1, 2). Bursts of synaptic activity can induce short term changes in synaptic strength, but more stable modifications typically require modulation of gene expression at the transcriptional and post-transcriptional levels (3, 4). Through post-transcriptional regulation, synaptic activity may dictate the time and place of neuronal protein synthesis.Regulated phosphorylation of translation factors and other ribosome-associated proteins is a major mechanism for controlling the activity of the translational machinery (5, 6). Translation control studies of LTP 2 have concentrated mainly on the Schaffer-collateral input to hippocampal CA1 pyramidal cells. Studies employing knock-out mice and pharmacological inhibitors support a role for eukaryotic initiation factor 4E (eIF4E) and eIF2␣ in consolidation of LTP in the CA1 region and long term memory (7-10). The function of the cap-binding protein eIF4E during translational initiation is controlled by eIF4E-binding proteins (4E-BPs), which inhibit initiation complex (eIF4F) formation by competing with the scaffolding protein eIF4G for...

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Osteogenic response to BMP‐2 of hMSCs grown on apatite‐coated scaffolds

Davis

Case

Miller

et al. 2011

Biotech & Bioengineering

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Osteoconductive materials play a critical role in promoting integration with surrounding bone tissue and resultant bone repair in vivo. However, the impact of 3D osteoconductive substrates coupled with soluble signals on progenitor cell differentiation is not clear. In this study, we investigated the influence of bone morphogenetic protein-2 (BMP-2) concentration on the osteogenic differentiation of human mesenchymal stem cells (hMSCs) when seeded in carbonated apatite-coated polymer scaffolds. Mineralized scaffolds were more hydrophilic and adsorbed more BMP-2 compared to nonmineralized scaffolds. Changes in alkaline phosphatase (ALP) activity within stimulated hMSCs were dependent on the dose of BMP-2 and the scaffold composition. We detected more cell-secreted calcium on mineralized scaffolds at all time points, and higher BMP-2 concentrations resulted in increased ALP and calcium levels. RUNX2 and IBSP gene expression within hMSCs was affected by both substrate and soluble signals, SP7 by soluble factors, and SPARC by substrate-mediated cues. The present data indicate that a combination of apatite and BMP-2 do not simply enhance the osteogenic response of hMSCs, but act through multiple pathways that may be both substrate- and growth factor-mediated. Thus, multiple signaling strategies will likely be necessary to achieve optimal bone regeneration.

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Dual regulation of translation initiation and peptide chain elongation during BDNF‐induced LTP in vivo: evidence for compartment‐specific translation control

Cited by 90 publications

References 52 publications

BDNF-induced local protein synthesis and synaptic plasticity

BDNF-induced local protein synthesis and synaptic plasticity

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Osteogenic response to BMP‐2 of hMSCs grown on apatite‐coated scaffolds

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