This is an individual National Research Service Award for pre-doctoral training for an M.D./Ph.D. student. By coupling to various intracellular cascades, metabotropic glutamate receptor 5 (mGluR5) plays an important role throughout the central nervous system (CNS) in modulating neuronal activity and synaptic transmission. Dysfunction of mGluR5 is implicated in a variety of neurological problems including anxiety, seizures, addiction, learning and memory disorders, and fragile X syndrome (FXS). In FXS, a single-gene disorder characterized by mental retardation and a range of autistic features, an expanded trinucleotide repeat results in a deficiency of fragile X mental retardation protein (FMRP). FMRP normally acts as a translational repressor to oppose mGluR5 signaling; thus, the lack of FMRP in FXS leads to overactivity of mGluR5. Although G-protein coupled receptors like mGluR5 are traditionally thought to initiate their signaling cascades from the cell surface, there is mounting evidence that intracellular receptors are also physiologically significant. This project will test the hypothesis that activation of intracellular mGluR5 versus cell surface mGluR5 has differential effects on protein synthesis and AMPA receptor (an excitatory ionotropic glutamate receptor) internalization in the hippocampus, an area important in learning and memory. Using sets of permeable and impermeable mGluR5 agonists and antagonists, activation of intracellular mGluR5 or cell surface mGluR5 can be achieved in isolation in order to delineate their downstream effects. For fragile X syndrome and possibly autism, understanding the role of intracellular mGluR5 will be crucial in developing suitable mGluR5 antagonists for therapeutic treatments.