A model of mTORC1 and mTORC2 activity at the synapse. mTOR interacts with distinct adaptor proteins forming mTORC1 and mTORC2 in the postsynaptic density. mTORC1 can be allosterically inhibited by the small molecule rapamycin bound to FKBP12. Chronic inhibition with rapamycin can indirectly lead to a down-regulation in mTORC2 activity. Both mTORC1 and mTORC2 can be acutely inhibited with kinase site inhibitors. In physiological contexts that are not conducive to growth (e.g., hypoxia, low energy, DNA damage, amino acid starvation), mTORC1 is kept in the “OFF-state” through the enhanced GAP activity of the TSC1/2 heterodimer. During amino acid starvation, the GATOR1 complex acts as a GAP for the Rag proteins. Under normal conditions and, indeed, during behavioral learning, mTORC1 and mTORC2 become active (“ON-state”). In this context, release of neurotransmitters from presynaptic neurons activates postsynaptic receptors (tyrosine-related kinase B [TrkB] in the case of homeostatic plasticity, mGluR and NMDAR during Hebbian stimulation), which leads to signal transduction through RAS and PI3K-dependent pathways. These signals converge at the surface of late endosomes where the resulting inhibition of TSC1/2 GAP activity allows charged RHEB to associate with PA-producing PLD1. The increased local concentration of PA leads to direct activation of mTORC1 activity. mTORC1 itself is localized to endosomal membranes via a Rag protein shuttle that is maintained through activation of the RAGulator, a protein complex whose activity is unlocked through structural rearrangement of a vacuolor–ATPase complex that is sensitive to amino acids. In contrast, mTORC2 is anchored to postsynaptic lipid rafts via Syndecan-4 (S4) and can be activated either directly through PI3K-dependent signaling or PLD1-synthesized PA. It is important to note that most of this model has been developed in nonneuronal cells, and therefore the relevance of mTOR localization in neurons has not been formally demonstrated. Moreover, although a postsynaptic density is pictured, this signaling can also occur presynaptically or in the cell soma. Green and red colors indicate active and inactive components, respectively.
