This is an individual National Research Service Award for post-doctoral research training, which provides support for promising Fellowship Applicants with the potential to become productive, independent investigators in scientific health-related research fields. Proper elimination of synapses is critical for neuronal development and function, and dysregulation of synaptic function has been implicated in multiple developmental disorders, including fragile X syndrome (FXS). The proposed studies will investigate the role of specific proteins in regulating neuronal interactions in a mouse model of FXS, which is caused by loss-of-function mutations in the fragile X mental retardation protein (FMRP). FMRP may control synaptic function and be key in synaptic elimination. Potential upstream effectors of FMRP- dependent synapse elimination are unclear. However, recent data demonstrate that an activity-dependent transcription factor, myocyte enhancer factor 2 (MEF2), regulates synapse elimination in CA1 hippocampal neurons. Interestingly, MEF2 has been genetically linked to autism-spectrum disorders, including FXS. MEF2-regulated mRNA transcripts include cytoskeletal protein Arc, which is translated in response to activation of group I metabotropic glutamate receptors (mGluRs). Electrophysiology and transfection of neurons with mutant forms of FMRP will be used to determine which features of FMRP-dependent translation are necessary for MEF2-dependent synapse elimination, and similar techniques will be used to investigate the role of group I mGluRs and Arc in this process. These data may provide a molecular mechanism for the increased spine density in FXS and reveal deficits in MEF2-dependent function in the disease. The results of these experiments may lead to the development of new therapies for autism and mental retardation disorders.