A. In normal (or wildtype) hippocampal CA1 neurons brief activation of mGluR1/5 triggers rapid endocytosis of AMPARs through TACE mediated intramembrane cleavage of NPR. mGluR-stimulated AMPAR endocytosis requires activity of the Tyr phosphatase STEP as well as existing Arc protein. MGluRs also trigger translation of proteins through activation of translation initiation, as well as dephosphorylation of the RNA binding protein, FMRP. Known proteins whose synthesis is stimulated by mGluRs as well as play a role in mGluR-LTD include Step, Map1b, Arc and APP. These proteins are known to regulate and/or stimulate AMPAR endocytosis. B. In the absence of FMRP, as in Fragile X Syndrome, mGluRs stimulate endocytosis of AMPARs, but it is unknown if the mechanisms are similar to those at normal synapses. In Fmr1 KO mice, there are increased steady state translation rates and protein levels of MAP1b and APP, as well as a deficit in mGluR stimulation of translation. mGluR-LTD in the Fragile X Syndrome mouse model (Fmr1 KO mice) is enhanced and independent of translation suggesting that the “LTD proteins” are available to maintain persistent decreases in AMPARs and LTD.