N-methyl-D-aspartate Receptor Mediates X-irradiation-induced Drebrin Decrease in Hippocampus

Background & Aims: Therapeutic X-irradiation of brain possibly causes cognitive impairment associated with synaptic dysfunction. Drebrin is a postsynaptic actin-binding protein and plays an important role for learning and memory. We have recently reported that drebrin decreases transiently in the molecular layer of dentate gyrus (MLDG) of hippocampus after X-irradiation in parallel with fear memory impairment. However, the mechanism regulating the drebrin decrease is not clarified. Our previous study has shown that activation of N-methyl-D-aspartate (NMDA) receptors induces transient drebrin exodus from dendritic spines. In the present study, we examined whether NMDA receptor relates to X-irradiation-induced drebrin decrease. Methods: Ten-week-old male mice, pretreated with an NMDA receptor antagonist MK801, were exposed to 10 Gy of whole brain X-irradiation and fixed after 8 hours. Immunostaining intensity of drebrin and PSD-95 in MLDG and number of doublecortin (DCX) positive neurons in dentate gyrus (DG) were analyzed. Results: X-irradiation decreased the intensity of drebrin and doublecortin-positive neurons. MK801 inhibited the decrease of drebrin intensity, but not the decrease of DCX-positive neurons. PSD-95 intensity did not change after irradiation. Conclusion: Our results indicate that NMDA receptor mediates the X-irradiation-induced decrease of drebrin, and suggest that NMDAR-mediated drebrin decrease underlies X-irradiation-induced acute transient cognitive impairment.