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Recent studies have demonstrated the presence of neurogenesis in the adult mammalian hippocampus, and it has been suggested that estrogen and various growth factors influence the processes of adult neurogenesis. The present study assessed cell proliferation in the dentate gyrus and the mRNA expression levels of granulin, insulin-like growth factor-I (IGF-I), and brain-derived neurotrophic factor (BDNF) in the hippocampus 4 h after treatment with estradiol benzoate (EB) in 3- and 12-month old ovariectomized rats. At 3 months of age, mRNA expression of granulin precursor and cell proliferation were increased by EB treatment, although the mRNA expressions of IGF-I and BDNF remained unchanged. At 12 months of age, however, neither mRNA expression of the three genes nor cell proliferation in the dentate gyrus were affected by EB treatment. In addition, 17beta-estradiol enhanced the proliferation of neural progenitor cells derived from hippocampal tissue of 3-month-old female rats in vitro; this was inhibited by neutralization of granulin with specific antibody. These results suggest that estrogen induces granulin gene expression in the hippocampus and that the product of this gene is involved in the mitogenic effects of estrogen in the dentate gyrus, although the responses to estrogen decline with age.

Involvement of Granulin in Estrogen-Induced Neurogenesis in the Adult Rat Hippocampus