A complex cascade of molecules downstream of glutamate (NMDA, AMPA, mGluR5) and BDNF receptors modulates FMRP activity at synapses. FMRP is affected by mTOR and Mnk1 signaling pathways (89) that regulate phosphorylation of general eIF4E-binding proteins and consequently protein synthesis. FMRP can be phosphorylated by S6 kinase (S6K) (72) or dephosphorylated by protein phosphatase 2A (PP2A) (137). The phosphorylation status affects its RNA-binding properties as well as its translational regulation. Mechanistically, FMRP has been shown to interact with the initiation factor eIF4E and regulate translational through the specific eIF4E-binding protein CYFIP1 (52). Further studies are required to verify whether FMRP also binds general eIF4E-BPs and whether these signaling pathways affect the FMRP-CYFIP1 complex as well. FMRP may also affect translational elongation (58). In absence of FMRP, the upstream kinase phosphatidylinositol 3-kinase (PI3K) is upregulated, leading to the increased mTOR phosphorylation and activity observed in patients with FXS as well as in the Fmr1 KO mouse (87, 89), culminating in an increased protein synthesis. Similar and possibly convergent effects are due to an upregulation of ERK (72, 87–89) and TrkB (85) signaling. In absence of FMRP, there is an increase of a subset of locally synthesized proteins (Arc, Map1B, αCAMKII, postsynaptic density-95 [PSD-95], MMP9, GSK-3β, among others). The increased Arc level contributes to an increased AMPA internalization and reduced AMPA in the membrane. At the same time, Arc, Map1B, PSD-95, and other dysregulated proteins involved in cytoskeleton scaffolding and remodeling may contribute to the FXS dysmorphic spine as well.