This is an NIH Pathway to Independence Award, which provides an opportunity for promising postdoctoral scientists to transition from mentored to independent research support. Fragile X syndrome (FXS) is the leading single gene cause of intellectual disability and autism. FXS is caused by mutations in the gene encoding the RNA binding protein fragile X mental retardation protein (FMRP). In the absence of FMRP, synaptic plasticity is altered. Both intellectual disability and autism likely result from impairments in a restricted set of neural circuits. This lab has recently described a novel structure, the Fragile X granule (FXG), that is expressed presynaptically in a subset of circuits, including some implicated in the etiology of autism such as frontal cortex, cerebellum and amygdala. Some of the symptoms of FXS and autism may arise from perturbations in presynaptic FMRP. These experiments will extend and deepen understanding of presynaptic FMRP and FXGs by characterizing the expression and activity-dependent regulation of presynaptic FMRP in vivo, identifying FXG-associated RNAs, and determining domains of FMRP required for FXG formation and presynaptic differentiation. Findings from these studies will elucidate how presynaptic FMRP contributes to normal cognition and how its loss contributes to the phenotypes observed in FXS and potentially autistic patients.