Fragile X syndrome (FXS), the leading cause of inherited mental retardation and the largest identified genetic basis for autism spectrum disorders, results from the lack of functional FMRP (fragile X mental retardation protein). One of the major anatomical phenotypes of the disorder is an alteration in the number and shape of dendritic spines, through which neurons communicate. This synaptic phenotype is seen both in human patients and in the mouse model of FXS. In typical individuals, the production and selective removal (pruning) of these connections gives rise to the development of an organized brain-wiring diagram that is guided by experience and learning. Interestingly, abnormal dendritic spines have been found in most forms of mental retardation as well as many other neurological conditions involving altered cognition. This finding suggests that either altered spines indicate an underlying connection failure or could themselves cause mental deficiencies. This project seeks to determine the underlying dynamics and structure of synaptic connections in FXS and how they arise during development. By monitoring synapses in living animals (mice) using 2-photon microscopy, the ontogeny and dynamic processes that lead to synaptic abnormalities seen in FXS can be determined, and the capacity for plasticity and potential for reversal of this system through intervention can be assessed. Model therapeutic treatments proposed include AAV-virus mediated restoration of FMRP expression as well as drug treatments including Lithium and specific metabotropic glutamate receptor antagonists. By reintroducing FMRP in both the adult and developing animal and comparing findings with nearly ideal restoration using another genetic mouse model, researchers will be able to determine how and when the phenotype arises and to what extent dynamic and structural phenotypes can be restored. Understanding the timing of FMRP's involvement will have significant implications for the development of treatments for FXS individuals, and determining the dynamic pattern of changes in spines after FMRP restoration will inform comparisons of pharmacological and viral-mediated treatments, each of which may alter dendritic spines in different ways.