Translational control of long-lasting synaptic plasticity and memory

Abstract

Long-lasting forms of synaptic plasticity and memory are dependent on new protein synthesis. Recent advances obtained from genetic, physiological, pharmacological, and biochemical studies provide strong evidence that translational control plays a key role in regulating long-term changes in neural circuits and thus long-term modifications in behavior. Translational control is important for regulating both general protein synthesis and synthesis of specific proteins in response to neuronal activity. In this review, we summarize and discuss recent progress in the field and highlight the prospects for better understanding of long-lasting changes in synaptic strength, learning, and memory and implications for neurological diseases.

Figure 1. Molecular Model for ATF4 mRNA Translational Control

The ATF4 mRNA (straight line), harbors uORFs 1 and 2 (green boxes). Upon translation of uORF1, the 80S ribosome dissociates and the 40S ribosomal subunit remains attached to the mRNA and resumes scanning in a 5′ to 3′ direction. (A) Under normal conditions, there is a sufficient supply of ternary complex (eIF2-Met-tRNA_i^Met-GTP), which rapidly associate with the 40S ribosomal subunit. This enables the 40S subunit to reinitiate translation at the AUG of uORF2. The 80S ribosome dissociates after terminating at uORF2. As the 40S ribosomal subunit cannot scan backward, the AUG codon of ATF4 cannot be translated. (B) Under conditions in which eIF2α is phosphorylated, the amount of ternary complex is reduced. Thus, a significant portion of scanning 40S ribosomal subunits scan pass the AUG of uORF2 and initiate at the AUG of ATF4.

Figure 2. mTOR Complex 1 and mTOR Complex 2 Signaling Network

The mTOR kinase is a component of two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In addition to mTOR, mTORC1 contains RAPTOR, mLST8, and PRAS40. mTORC1’s activity is modulated by the PI3K/Akt signaling pathway. Akt phosphorylates and inhibits TSC2, which leads to activation of Rheb, which in turns activates mTORC1. Akt also phosphorylates PRAS40. mTORC1 activation releases mTORC1 from PRAS40 repression and leads to phosphorylation of 4E-BPs and S6K. mTORC2 contains mLST8, RICTOR, mSIN1. The best-characterized substrate of mTORC2 is the AKT kinase.