Psychiatric disorders exhibit abnormal dendritic structure and/or alterations in dendritic spine morphology. However, little is known about the potential effects of brain irradiation on dendritic spines in the hippocampus in young adult animals. A better knowledge of how cranial irradiation affects dendritic spines in hippocampal sub regions could provide critical information regarding the mechanism of disruption of neural circuitry following radiation exposure. The purpose of the present study was to determine the temporal effects of cranial irradiation on spine density and morphology in the dendrites of granule neurons of dentate gyrus as well as pyramidal neurons of CA1 area of the hippocampus. Since pyramidal neurons typically consist of apical and basal dendrites which differ in their connectivities, biophysical characteristics and long term potentiation induction and expression mechanisms, spine analyses were conducted separately in the apical and basal dendrites. To the best of our knowledge, no previous experiments have specifically addressed temporal and region specific effects of cranial irradiation on spine density and morphology in the hippocampus in young adult animals. Therefore, this was designed as a proof of concept study using a dose of irradiation that has been shown to cause hippocampal dependent cognitive impairment, so as to determine if changes in dendritic spines might offer a specific target for better understanding the effects of irradiation on cognition. The present study demonstrated that brain irradiation altered spine density as well as the proportion of morphological subtypes in the dendrites of DG granule neurons and basal dendrites of CA1 pyramidal neurons in a time dependent manner. While there was a gradual decrease in spine density in the DG over time, spine density in the CA1 basal dendrites decreased at 1 week post irradiation with a trend toward recovery at 1 month. Additionally, in the CA1 apical dendrites, irradiation altered spine morphology without any change in spine density at both 1week and 1month post irradiation. To our knowledge, these results are the first to demonstrate that, in young adult mice, cranial irradiation affects dendritic spine density and morphology in the hippocampus in a temporal and region specific manner. The maintenance of normal brain function is dependent on the establishment and efficient maturation of synaptic circuits. The hippocampus plays a key role in learning and memory processes and is particularly susceptible to the effects of ionizing irradiation. While irradiation has been shown to change the numbers of newly born neurons in the DG, data also exist showing changes associated with learning and memory that do not involve overt mature neuronal loss. This latter finding suggests that changes in structure and function of viable neuronal cells may play an important role in the development of cognitive deficits after irradiation, and highlights the potential importance of assessing critical structures such as dendritic spines. Dendritic spines are the primary FTY720 recipients of excitatory input in the CNS, and changes in spine density and morphology can account for functional differences at the synaptic level. Spine morphology can predict both spine stability and synaptic strength and findings from in vivo models support the notion that structural plasticity of spines is related to learning and memory function. In light of the multiple spine functions, pathological changes in spine number and structure may have significant consequences for brain function, as has been shown in studies of stress, malnutrition, toxins and drugs of abuse.