Mechanisms of translation control underlying long-lasting synaptic plasticity and the consolidation of long-term memory

Abstract

The complexity of memory formation and its persistence is a phenomenon that has been studied intensely for centuries. Memory exists in many forms and is stored in various brain regions. Generally speaking, memories are reorganized into broadly distributed cortical networks over time through systems level consolidation. At the cellular level, storage of information is believed to initially occur via altered synaptic strength by processes such as long-term potentiation. New protein synthesis is required for long-lasting synaptic plasticity as well as for the formation of long-term memory. The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of cap-dependent protein synthesis and is required for numerous forms of long-lasting synaptic plasticity and long-term memory. As such, the study of mTORC1 and protein factors that control translation initiation and elongation has enhanced our understanding of how the process of protein synthesis is regulated during memory formation. Herein we discuss the molecular mechanisms that regulate protein synthesis as well as pharmacological and genetic manipulations that demonstrate the requirement for proper translational control in long-lasting synaptic plasticity and long-term memory formation.

Keywords: 4E-BP; Consolidation; Long-term potentiation; Memory; Protein synthesis; S6K1; eIF2α; eIF4E; mTOR.

Figure 1. The reorganization of memory occurs with the passage of time

Learning occurs within hours and is initially stored in local synaptic circuits. This “synaptic consolidation” persists for days and up to weeks. Synaptic consolidation is gradually converted to systems consolidation, where the memory can persist for years, in broadly distributed cortical networks.

Figure 2. LTP: A cellular substrate for memory formation

A) Hippocampal LTP can be induced by high-frequency stimulation of the Schaffer Collateral pathway. Shown is a diagram of a stimulating electrode, which is placed near the axonal tract originating from CA3 pyramidal neurons, and a recording electrode, which is placed in the dendritic tree of CA1 pyramidal neurons. B) E-LTP and L-LTP induction is achieved using high-frequency stimulation. Early phase LTP (E-LTP) is induced by 1 train of high frequency stimulation (HFS) and long-lasting, late phase LTP (L-LTP) is induced using 4 spaced trains of HFS. E-LTP persists approximately 1 hour, whereas L-LTP persists for several hours.

Figure 3. mTOR exists in two complexes

mTORC1 is comprised of mTOR, raptor, LST8 and PRAS40. mTORC2 is comprised of mTOR, rictor, LST8 and sin1.]

Figure 4. The phosphorylation of 4E-BP by mTORC1 leads to the formation of eIF4F, the cap-dependent translation initiation complex

The eIF4 group of eIFs form the cap-binding complex eIF4F, which consists of the cap-binding protein eIF4E, the DEAD-box RNA helicase eIF4A, and the scaffolding protein eIF4G. eIF4G circularizes the mRNA by interacting simultaneously with eIF4E and PABPs.