Translational control in synaptic plasticity and cognitive dysfunction

Abstract

Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.

Keywords: autism; eIF2α; local protein synthesis; mTOR; memory; neurodegeneration.

Figure 1

Translation initiation in neurons. Translation intitiation, often the rate-limiting step in protein synthesis, involves multiple fundamental reactions. These include formation of the 43S preinitiation complex, ribosomal scanning along the mRNA, AUG initiation codon recognition, and subunit joining to form the 80S ribosomal complex. Following 80S formation, translation elongation factors are recruited to elongate the forming polypeptide chain. Once the stop codon is reached, the elongation factors are disengaged and release of the newly synthesized protein is orchestrated through the action of translation termination factors.

Figure 2

The key signaling pathways that regulate activity-dependent translation initiation in neurons. (a) Synaptic activity triggers dephosphorylation of initiation factor eIF2α by either activation of eIF2α-specific phosphatase complexes or inhibition of the eIF2α kinases. Dephosphorylation of eIF2α is both sufficient and necessary to induce L-LTP and LTM formation. In glutamatergic neurons, phosphorylation of eIF2α promotes translation of ATF4, a CREB repressor. PKR-mediated phosphorylation of eIF2α in GABAergic neurons negatively regulates translation of the inflammatory cytokine IFN-γ, thus promoting GABA release and maintaining low network rhythmicity in the absence of significant stimulatory inputs. (b) Cap-dependent translation is mediated through mTORC1-dependent phosphorylation of its primary downstream effectors, the 4E-BPs and S6Ks. mTORC1 activity is driven by excitatory synaptic inputs, in addition to other cellular signals, that engage the PI3K/Akt signaling pathway. (c) Calcium influx following NMDAR activation triggers degradation of Paip2 by calcium-activated calpains, thus releasing PABP to bind eIF4G. The eIF4G-PABP complex then contributes to mRNA circularization by directly bridging the elongated 3′ poly(A) tail to the eIF4F complex at the 5′ cap. Cap-dependent translation is initiated upon subsequent recruitment of the 40S and 60S ribosomal complexes. Abbreviations: GADD34, growth arrest and DNA damage-inducible protein; CReP, constitutive reverter of eIF2α phosphorylation; CREB, cAMP response element-binding protein; PI3K, phosphatidylinositide 3-kinase; PDK1, phosphoinositide-dependent kinase-1.