Introduction:The response of the brain to space radiation is an important concern for astronauts during space missions. Therefore, we assessed the response of the brain to28Si ion irradiation (600 MeV/n), a heavy ion present in the space environment, on cognitive performance and whether the response is associated with altered DNA methylation in the hippocampus, a brain area important for cognitive performance.Methods:We determined the effects of28Si ion irradiation on object recognition, 6-month-old mice irradiated with28Si ions (600 MeV/n, 0.3, 0.6, and 0.9 Gy) and cognitively tested two weeks later. In addition, we determined if those effects were associated with alterations in hippocampal networks and/or hippocampal DNA methylation.Results:At 0.3 Gy, but not at 0.6 Gy or 0.9 Gy,28Si ion irradiation impaired cognition that correlated with altered gene expression and 5 hmC profiles that mapped to specific gene ontology pathways. Comparing hippocampal DNA hydroxymethylation following proton,56Fe ion, and28Si ion irradiation revealed a general space radiation synaptic signature with 45 genes that are associated with profound phenotypes. The most significant categories were glutamatergic synapse and postsynaptic density.Discussion:The brain’s response to space irradiation involves novel excitatory synapse and postsynaptic remodeling.