A model of signaling pathways downstream of mTORC1 and mTORC2 that regulate synaptic plasticity. In addition to canonical receptor-mediated signaling, the activation of mTORC1 following synaptic stimulation can be enhanced indirectly through mTORC2-mediated cotranslational stabilization of AKT. Translation of both LTP- and LTD-target mRNAs is targeted following mTORC1 activation. Release of 4EBP-mediated repression preferentially stimulates translation initiation of TOP mRNAs, while release of eEF2K-mediated repression through S6K stimulates translation elongation of LTP-target mRNAs. While S6K also targets ribosomal protein S6 and eIF4B (not shown), their roles in synaptic plasticity are unknown. Many mRNAs that are required for LTD have an additional level of translation repression in the form of FMRP. FMRP is thought to repress translation by promiscuously binding to the coding sequence of the mRNA, thus preventing ribosomal translocation, perhaps through blocking the activity of eEF2. By acting as a brake, this protein impedes translation of LTD-target mRNAs despite mTORC1-dependent stimulation of translation. On the other hand, stimulation of mGluR receptors leads to activation of the phosphatase PP2A, which transiently inactivates FMRP activity, releasing the brake. This allows subsequent mTOR-dependent stimulation of LTD target mRNA translation at the expense of LTP target mRNAs. Sustained stimulation resets FMRP activity through S6K-mediated phosphorylation, allowing for the replenishment of the LTD-target mRNA pool. mTORC1-dependent protein synthesis can translate mRNAs encoding retrograde signals to increase presynaptic strength. However, mTORC1 activation during LTP and LTD is not sufficient to mediate synaptic plasticity and requires additional signaling. One step required for LTP may be activation of the RAC1–PAK1 pathway by mTORC2 that leads to inhibition of the actin depolymerase, Cofilin. Alternatively, actin stabilization may be important upstream of mTORC1 for activation of the translational control pathway. The combined result of mTORC1- and mTORC2-signaling during LTP or LTD is mediated by altered trafficking of AMPA receptors and changes in the synaptic architecture. Green and red colors indicate active and inactive components, respectively.
