Fragile X Syndrome (FXS) is the most common neurodevelopmental disorder associated with intellectual disabilities. In FXS, an increased CGG triplet repetition in the fmr1 gene, cause the hypermethylation of the 5’UTR and, in turn leads to the gene silencing and the absence of the Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein, able to regulate the expression of different RNAs and fundamental for synapses function. FMRP is expressed in neurons but also in astrocytes and microglia, the other key cells of the brain. Despite many studies have focused their attentions on the role of FMRP in neurons, only a few pieces of evidences have reported the role of the protein in other brain cells types. In preliminary results, performed by immunofluorescence or western blot analysis in fmr1ko mice, we revealed an hyperactivated state of microglia, measured with phagocytic marker CD68, an increase of synaptic material engulfed in microglia and an increase of microglia-specific transcriptor factor PU.1/Spi1. Interestingly, activated microglia is present in many neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis. Increase level of transcriptional factor PU.1 in fmr1ko mice suggest an unbalance of epigenetic mechanism occurring in microglia cells and an alteration of microglia in absence of FMRP. This approach will be instrumental to identify new molecular pathways responsible for the activated-state of microglia in fmr1ko mice and suggest that modulating PU.1 expression may be a valid therapeutic target to prevent microglial-mediated hyperactivation in fmr1ko mice model.