P53 is a tumour suppressor protein thought to be primarily involved in cancer biology, but recent evidence suggests it may also coordinate novel functions in the CNS, including mediation of pathways underlying neurodegenerative disease. In microglia, the resident immune cells of the brain, p53 activity can promote an activation-induced pro-inflammatory phenotype Jayadev et al. (2011) [1], as well as neurodegeneration Davenport et al. (2010) [2]. Synapse degeneration is one of the earliest pathological events in many chronic neurodegenerative diseases Conforti et al. (2007) and Clare et al. (2010) [3], [4] and may be influenced by early microglial responses. Here we examined synaptic properties of neurons following modulation of p53 activity in rat microglia exposed to inflammatory stimuli. A significant reduction in the expression of the neuronal synaptic markers synaptophysin and drebrin, occurred following microglial activation and was seen prior to any visible signs of neuronal cell death, including neuronal cleaved caspase-3 activation. This synaptic marker loss together with microglial secretion of the inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1-β (IL-1β) was abolished by the removal of microglia or inhibition of microglial p53 activation. These results suggest that transcriptional-dependent p53 activities in microglia may drive a non-cell autonomous process of synaptic degeneration in neurons during neuroinflammatory degenerative diseases.