BDNF-induced local protein synthesis and synaptic plasticity
By combining exercise with antidepressants (which increase the expression of the long-lasting form), scientists were able to both increase and accelerate the production of BDNF.
Spike-timing stimulation (A) induced spine-head enlargement (B), which was dependent on protein synthesis (C) and selective to stimulated spine.
BDNF Stimulation of Protein Synthesis in Cortical …
and (1996) A Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity. Science, 273 (5280). pp. 1402-1406. ISSN 0036-8075.
Two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are able to produce a long-lasting enhancement of synaptic transmission in the hippocampus. Unlike other forms of plasticity, neurotrophin-induced plasticity exhibited an immediate requirement for protein synthesis. Plasticity in rat hippocampal slices in which the synaptic neuropil was isolated from the principal cell bodies also required early protein synthesis. Thus, the neurotrophins may stimulate the synthesis of proteins in either axonal or dendritic compartments, allowing synapses to exert local control over the complement of proteins expressed at individual synaptic sites.
In the absence of protein synthesis, BDNF seems to …
Although the MNKs have been implicated in protein synthesis-dependent synaptic plasticity (, ), their function in translational regulation remains obscure. Here, we show that BDNF-induced stimulation of protein synthesis in primary cortical neurons requires MEK/ERK signaling and MNK1. Furthermore, MNK1 is necessary for BDNF-induced release of CYFIP1 from an m7GTP resin, which captures eIF4E and associated proteins. Finally, using a novel combination of bio-orthogonal noncanonical amino acid tagging (BONCAT; ) and stable-isotope labeling in cell culture (SILAC; ), we identify a subset of proteins whose synthesis is regulated by BDNF in an MNK1-dependent manner. Strikingly, many are encoded by mRNAs that bind FMRP.
The availability of eIF4E to bind to eIF4G and initiate translation is inhibited by its interaction with eIF4E-binding proteins, 4E-BPs, of which the most abundant in brain is 4E-BP2 (). 4E-BP2 is phosphorylated by mTORC1 (B). eIF4E also interacts in a translationally repressive manner with cytoplasmic fragile X mental retardation protein (FMRP)-interacting protein, CYFIP1 (). CYFIP1 binds FMRP (C), a translational repressor protein which interacts with numerous mRNAs involved in regulating synaptic function (). In neuronal cells, BDNF causes release of CYFIP1 from eIF4E, thereby regulating mRNA translation ().
BDNF: A key regulator for protein synthesis-dependent …
Translation: Making Protein Synthesis Possible
Protein synthesis is required for consolidation of memory and has been used to characterize memory systems
BDNF-induced local protein synthesis and synaptic plasticity
BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1.
Independence of BDNF effect on protein synthesis
Protein Synthesis-dependent and -independent Regulation of Hippocampal Synapses by Brain-derived Neurotrophic Factor
Protein synthesis and neurotrophin-dependent …
The data obtained using pharmacological inhibitors indicated that the MNKs are important in the BDNF-induced increase in protein synthesis in neuronal cells. To study this further, without the need to use such compounds and to examine potentially unique contributions of MNK1 and MNK2 to the observed effects, we made use of cortical neurons derived from WT, MNK1 KO, MNK2 KO, or MNK1/2 DKO mice (). BDNF caused an increase in eIF4E phosphorylation in neurons from WT or MNK2 KO mice, but not in cells from MNK1 KO mice (A,B). As expected, no phosphorylation of eIF4E was seen in cells from DKO animals (data not shown). The BDNF-induced increases in ERK, PKB, and S6 phosphorylation were not affected in either MNK1 or MNK2 KO neurons (A,C–E). Interestingly, BDNF treatment resulted in a trend toward a decrease in eIF4E phosphorylation in neurons from MNK1 KO mice (A,B) suggesting that BDNF may also stimulate a negative regulator of eIF4E phosphorylation. Finally, the BDNF-induced increase in overall rates of protein synthesis was observed in neurons derived from WT and MNK2 KO mice, but no increase was seen in cells from MNK1 KO or MNK1/2 DKO mice (F).
Translation initiation can be regulated via alterations in the binding of eIF4E with small 4E-binding phosphoproteins (4E-BPs) that block its ability to bind to eIF4G (). Furthermore, BDNF stimulation has been found to result in both an increase in 4E-BP2 phosphorylation (), a mechanism that is important for the release of 4E-BP2 from eIF4E, and in a decrease in the binding of eIF4E with CYFIP1 (; ). Using affinity chromatography on immobilized m7GTP to isolate eIF4E and associated proteins, we observed that BDNF caused a decrease in the binding of 4E-BP2 and CYFIP1 to the m7GTP resin (A,B). BDNF-induced 4E-BP2 release was prevented by prior incubation of neurons with rapamycin (C), an mTORC1 inhibitor, but this effect was insensitive to inhibition of the MNKs by MNK-I1 (D), and was intact in neurons derived from WT, MNK1 KO or MNK2 KO mice (E).
A Requirement for Local Protein Synthesis in …
Although CGP57380 is often used as a MNK inhibitor, it also inhibits several other kinases at similar concentrations in vitro (). Thus, we used the more recently characterized compound, MNK-I1, that is both more potent and has greater specificity than CGP57380 (J. Beggs, G.G. Jones, S. Tian, J. Xie, V. Iadevaia, V. Jenei, G. Thomas, C.G. Proud, unpublished observations). As observed for CGP57380, MNK-I1 decreased basal eIF4E phosphorylation and prevented the BDNF-induced increase in eIF4E phosphorylation (E) without affecting ERK, PKB, or mTORC1 signaling (E,G). MNK-I1 also prevented the BDNF-induced increase in protein synthesis (H).). Interestingly, we noticed a potential small decrease in overall levels of eIF4E by the combined application of BDNF and MNK-I1 (F; see also 6D,G), although we did not consistently see this throughout our experiments (data not shown). Although it is not altogether clear what might be mediating this subtle decrease, it does not affect the interpretation of the data as the m7-GTP pull-downs are normalized to total eIF4E levels.