The Alzheimer's disease drug memantine increases the number of radial glia‐like progenitor cells in adult hippocampus

Abstract

New neurons are continuously generated in the hippocampus of the adult mammalian brain, and N-methyl-D-aspartate receptor (NMDA-R) antagonists have been found to increase the number of newly generated neurons in the dentate gyrus (DG) of the adult hippocampus. In this study, we examined the effect of memantine, an NMDA-R antagonist that is clinically used for the treatment of Alzheimer's disease, on primary progenitor cells exhibiting a radial glia-like (RGL) morphology in the DG. We injected 3-month-old mice with memantine (50 mg/kg body weight, intraperitoneally [i.p.]); 3 days later, we injected the mice with 5-bromo-2-deoxyuridine (BrdU; 75 mg/kg body weight, i.p.). We then counted the number of BrdU-labeled RGL progenitor cells in the DG 1 or 7 days after the BrdU-injection. The number of BrdU-labeled RGL progenitor cells had increased significantly by 5.1-fold on day 1 and by 13.7-fold on day 7 after BrdU-injection. Immunohistochemical staining revealed that the BrdU-labeled RGL progenitor cells expressed two primary progenitor cell marker proteins, nestin and Sox2. These results clearly demonstrated that memantine promotes the proliferation of RGL progenitor cells. We also found that memantine increased the ratio of horizontally aligned RGL progenitor cells, which are probably produced by symmetric division. These findings suggest that memantine increases the proliferation of primary progenitor cells and expands the primary progenitor cell pool in the adult hippocampus by stimulating symmetric division.