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  • Review Article
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Biochemical mechanisms for translational regulation in synaptic plasticity

Key Points

  • Translation factors and translational control mechanisms are downstream targets of several signalling pathways and are crucial in synaptic plasticity. Some forms of translational control alter general protein synthesis, whereas others regulate translation of specific messenger RNAs (mRNAs).

  • Translation initiation refers to the assembly of a translation-competent ribosome at the AUG start codon on an mRNA. The first step involves the binding of the translation-initiation factor eIF2, which is a G protein, to methionyl-transfer RNA in a GTP-dependent manner.

  • eIF2 has three subunits (α, β and γ), and the conversion of inactive eIF2·GDP to active eIF2·GTP by eIF2B is blocked by phosphorylation of eIF2α. Four kinases that are present in the brain — PKR, HRI, PERK and GCN2 — phosphorylate eIF2α on Ser51.

  • The eIF2B enzyme complex consists of five polypeptides (α–ε), with eIF2Bε catalysing guanine nucleotide exchange on eIF2. The importance of eIF2B function in the brain is highlighted by the fact that mutations in each eIF2B subunit can cause leukoencephalopathy with vanishing white matter.

  • The integrity of the eIF4F cap-binding complex and, therefore, translation efficiency, is regulated by 4E-BPs. Phosphorylation of 4E-BPs by the extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signalling pathways is crucial for protein synthesis-dependent synaptic plasticity and memory.

  • The cap-binding protein eIF4E is phosphorylated by the protein kinases Mnk1 and Mnk2, which are phosphorylated and activated by ERK and p38. eIF4E phosphorylation is associated with synaptic plasticity and memory.

  • In addition to regulating 4E-BP phosphorylation and function, mTOR directly phosphorylates and activates the S6 kinase (S6K), which phosphorylates the ribosomal protein S6, an essential component of the small, 40S ribosomal subunit. S6K and S6 phosphorylation have been implicated in synaptic plasticity and memory.

  • The cytoplasmic polyadenylation element (CPE) in the 3′-untranslated region is important in extension of the poly(A) tail and translation activation. Recent evidence indicates a crucial role for CPE-binding protein in long-term facilitation in Aplysia californica and in hippocampal synaptic plasticity.

Abstract

Changes in gene expression are required for long-lasting synaptic plasticity and long-term memory in both invertebrates and vertebrates. Regulation of local protein synthesis allows synapses to control synaptic strength independently of messenger RNA synthesis in the cell body. Recent reports indicate that several biochemical signalling cascades couple neurotransmitter and neurotrophin receptors to translational regulatory factors in protein synthesis-dependent forms of synaptic plasticity and memory. In this review, we highlight these translational regulatory mechanisms and the signalling pathways that govern the expression of synaptic plasticity in response to specific types of neuronal stimulation.

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Figure 1: Pathway of translation initiation in eukaryotes.
Figure 2: Recycling of eIF2 by eIF2B and regulation by the eIF2α kinases.
Figure 3: Signalling pathways that are involved in translational regulation in L-LTP and mGluR-dependent LTD.
Figure 4: Regulation of translation initiation by polyadenylation after NMDA receptor activation.

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Acknowledgements

We thank J. Richter and N. Sonenberg for communicating unpublished results, and J. Banko for helpful comments on the manuscript. E.K. is supported by the National Institutes of Health and the Fragile X (FRAXA) Research Foundation.

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DATABASES

Entrez Gene

ARC

BDNF

bicoid

CPEB

eEF1A

eEF2

eIF1

eIF1A

eIF2α

eIF2B

eIF3

eIF4A

eIF4B

eIF4E

eIF4F

eIF4G

eIF5

eIF5B

FMRP

FOS

GCN2

GSK3β

Mnk1

Mnk2

Nanos

Orb

oskar

PABP

Pumilio

S6K1

Staufen

OMIM

VWM

FURTHER INFORMATION

Encyclopedia of Life Sciences

Learning and memory

Protein phosphorylation and long-term synaptic plasticity

Protein synthesis and long-term synaptic plasticity

Eric Klann's homepage

Thomas Dever's homepage

Glossary

LONG-TERM FACILITATION

(LTF). A cellular analogue of long-term memory in Aplysia that can be induced at Aplysia sensory–motor synapses with multiple, spaced pulses of serotonin.

LONG-TERM POTENTIATION

(LTP). A putative cellular model for memory that is manifested as a long-lasting increase in synaptic strength. LTP is most often induced with high-frequency stimulation of afferent inputs.

LATE-PHASE LTP

(L-LTP). Transcription- and translation-dependent LTP that is typically induced with multiple, spaced trains of high-frequency stimulation. This type of LTP persists for more than 3 hours.

SHORT-TERM FACILITATION

(STF). A cellular analogue of short-term memory in Aplysia that can be induced at Aplysia sensory–motor synapses with one pulse of serotonin.

EARLY-PHASE LTP

(E-LTP). Transcription- and translation-independent LTP that is typically induced with one train of high-frequency stimulation. This type of LTP persists for 1–3 hours.

LONG-TERM DEPRESSION

(LTD). A long-lasting decrease in synaptic strength that can be induced in hippocampal area CA1 by either low-frequency stimulation (NMDA receptor-dependent) or stimulation of group I metabotropic glutamate receptors.

GENERAL CONTROL NON-DEREPRESSIBLE 4

(GCN4). A yeast transcription factor. Its expression is controlled by eIF2α phosphorylation, which regulates re-initiation at the upstream open reading frames in the GCN4 messenger RNA.

ACTIVATING TRANSCRIPTION FACTOR 4

(ATF4). A mammalian transcription factor whose expression is regulated by eIF2α phosphorylation and upstream open reading frames, like GCN4 in yeast.

INTERNAL RIBOSOMAL ENTRY SITE

(IRES). A messenger RNA (mRNA) sequence that directs 5′-cap-independent binding of the 40S subunit to an mRNA.

ASSOCIATIVE FEAR CONDITIONING

An associative learning model in which the animal learns to associate a neutral conditioned stimulus (CS) with an aversive unconditioned stimulus (US). In many fear conditioning studies with rats and mice, the presentation of a harmless acoustic cue (CS) is paired with a mild foot shock (US) in a novel environment. At some point after training, the animals are tested for fear (usually freezing) in response to presentation of either the context (contextual fear conditioning) or the CS delivered in a novel context (cued fear conditioning). Both types of fear conditioning depend on the amygdala, whereas contextual fear conditioning also depends on the hippocampus.

TERMINAL OLIGOPYRIMIDINES

(TOP). Messenger RNAs (mRNAs) that typically encode ribosomal proteins or translation factors. These mRNAs are translationally regulated through their 5′-terminal oligopyrimidine tracts.

PRION

A protein that folds into two alternate conformations with different functions, wherein one conformation is self-perpetuated through conversion of the protein in the other confirmation.

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Klann, E., Dever, T. Biochemical mechanisms for translational regulation in synaptic plasticity. Nat Rev Neurosci 5, 931–942 (2004). https://doi.org/10.1038/nrn1557

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