BDNF + Protein Synthesis = Synaptic Plasticity

2008 ◽  
Vol 1 (12) ◽  
pp. ec112-ec112
Author(s):  
P. Stern
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

scholarly journals Multiple components of eIF4F are required for protein synthesis-dependent hippocampal long-term potentiation

2013 ◽  
Vol 109 (1) ◽  
pp. 68-76 ◽  
Author(s):  
Charles A. Hoeffer ◽  
Emanuela Santini ◽  
Tao Ma ◽  
Elizabeth C. Arnold ◽  
Ashley M. Whelan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Translational Control ◽  
Late Phase ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
General Protein Synthesis ◽  
General Protein

Persistent forms of synaptic plasticity are widely thought to require the synthesis of new proteins. This feature of long-lasting forms of plasticity largely has been demonstrated using inhibitors of general protein synthesis, such as either anisomycin or emetine. However, these drugs, which inhibit elongation, cannot address detailed questions about the regulation of translation initiation, where the majority of translational control occurs. Moreover, general protein synthesis inhibitors cannot distinguish between cap-dependent and cap-independent modes of translation initiation. In the present study, we took advantage of two novel compounds, 4EGI-1 and hippuristanol, each of which targets a different component of the eukaryotic initiation factor (eIF)4F initiation complex, and investigated their effects on long-term potentiation (LTP) at CA3-CA1 synapses in the hippocampus. We found that 4EGI-1 and hippuristanol both attenuated long-lasting late-phase LTP induced by two different stimulation paradigms. We also found that 4EGI-1 and hippuristanol each were capable of blocking the expression of newly synthesized proteins immediately after the induction of late-phase LTP. These new pharmacological tools allow for a more precise dissection of the role played by translational control pathways in synaptic plasticity and demonstrate the importance of multiple aspects of eIF4F in processes underlying hippocampal LTP, laying the foundation for future studies investigating the role of eIF4F in hippocampus-dependent memory processes.

scholarly journals Rates of protein synthesis are reduced in peripheral blood mononuclear cells (PBMCs) from fragile X individuals

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251367
Author(s):  
Olivier Dionne ◽  
Audrey Lortie ◽  
Florence Gagnon ◽  
François Corbin
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Intellectual Disability ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Fragile X ◽  
General Mechanism ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Background Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterized. Method We applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals. Results Using this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method. Conclusion Our work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.

scholarly journals Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Alan Jung Park ◽  
Mahesh Shivarama Shetty ◽  
Jay M. Baraban ◽  
Ted Abel
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Local Protein Synthesis ◽  
Hippocampal Synaptic Plasticity ◽  
Behavioral Abnormalities ◽  
Local Protein

Abstract Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, translin knockout (KO) mice, which lack translin/trax, exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome (fragile X mental retardation protein-FMRP-KO mice). Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic protein kinase A (PKA) activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression (mGluR-LTD), a hallmark of the FMRP KO mice. On the contrary, translin KO mice exhibited deficits in N-methyl-d-aspartate receptor (NMDAR) dependent LTD, a phenotype not observed in the FMRP knockouts. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling and suggest that translin/trax and FMRP play distinct roles in hippocampal synaptic plasticity.

scholarly journals BDNF-induced local protein synthesis and synaptic plasticity

2014 ◽  
Vol 76 ◽  
pp. 639-656 ◽  
Author(s):  
Graciano Leal ◽  
Diogo Comprido ◽  
Carlos B. Duarte
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Local Protein Synthesis ◽  
Local Protein

scholarly journals Signaling Mechanisms Mediating BDNF Modulation of Synaptic Plasticity in the Hippocampus

1999 ◽  
Vol 6 (3) ◽  
pp. 243-256 ◽  
Author(s):  
Wolfram A. Gottschalk ◽  
Hao Jiang ◽  
Nicole Tartaglia ◽  
Linyin Feng ◽  
Alexander Figurov ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Neurotrophic Factor ◽  
High Frequency ◽  
Hippocampal Slices ◽  
Close Relative ◽  
Signaling Mechanisms ◽  
Neurotrophin 3 ◽  
Neurotrophin Signaling

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-γ (PLC-γ) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-γ. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-γ, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.

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