Dysregulated mTORC1-Dependent Translational Control: From Brain Disorders to Psychoactive Drugs

Abstract

In the last decade, a plethora of studies utilizing pharmacological, biochemical, and genetic approaches have shown that precise translational control is required for long-lasting synaptic plasticity and the formation of long-term memory. Moreover, more recent studies indicate that alterations in translational control are a common pathophysiological feature of human neurological disorders, including developmental disorders, neuropsychiatric disorders, and neurodegenerative diseases. Finally, translational control mechanisms are susceptible to modification by psychoactive drugs. Taken together, these findings point to a central role for translational control in the regulation of synaptic function and behavior.

Keywords: S6K1; developmental disorders; eIF4E; mTORC1 signaling; neurodegenerative diseases; protein synthesis; psychoactive drugs; translation initiation.

Figure 1

Schematic of mTOR signaling pathways. Activation of neuronal receptors and channels (mGluRs, NMDARs, TrkB, D1Rs, and D2Rs) leads to activation of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 activation increases some neuronal processes (protein synthesis) while inhibiting others (autophagy). mTORC1 regulates the activity of downstream effectors involved in translation (S6K1, 4E-BP2), some of which are also directly phosphorylated via convergent activation of the MAPK signaling pathway (S6K1, MnK, S6). mTORC1-dependent phosphorylation of 4E-BP2 results in the association of eIF4E with eIF4G and the formation of the active eIF4F (eIF4E–eIF4A–eIF4G) complex. eIF4F recruits eIF4B and MnK and promotes the binding of mRNAs to the 43S pre-initiation complex to form the 48S initiation complex. The eIF4F complex and the poly(A) tail act synergistically together with MnK-dependent phosphorylation of eIF4E to stimulate cap-dependent translation initiation. The signaling pathways that activate mTORC2 and its downstream effectors, as well as its physiological functions are currently unknown. Black solid arrows indicate direct phosphorylation/activation, pink double arrows represent molecular association/dissociation and blue lines indicate inhibition.

Figure 2

Schematic of FMRP regulation of cap-dependent translation initiation. FMRP represses the translation of specific mRNAs via interaction with a 4E-BP-like protein termed CYFIP1, which also binds eIF4E. One of the mRNAs regulated by FMRP is encoding for PIKE, which enhances PI3K signaling. In fragile X syndrome (FXS), the absence of functional FMRP results in the abnormal translation of PIKE and other mRNAs. Indeed, in FXS model mice PI3K/mTORC1 signaling is enhanced. Note that activation of surface receptors (i.e., group I mGluRs) promotes PI3K signaling via PIKE and activation of mTORC1-dependent protein synthesis. Activation of mTORC1 may also induce translation of FMRP-dependent mRNAs via an unknown mechanism. Black solid arrows indicate direct phosphorylation/activation, dashed arrows represent events mediated by unknown molecular effectors.