Abstracts

Previous studies have suggested that genetic factors can modulate adult hippocampal neurogenesis (Zhao et al., 2003; Kempermann and Gage, 2002). However, the links between perturbations in neurogenesis and genomic control are unclear. To investigate the degree to which genetic strain differences influence adult dentate granule cell neurogenesis and the stage(s) of the neurogenic program that is affected, we examined proliferating progenitor cells and their progeny in young male FVB/N and C57BL/6 mice using the thymidine analog, bromodeoxyuridine (BrdU). Six-week old male C57BL/6 and FVB/N mice were obtained and given two daily BrdU injections, 6 hours apart, and were killed 1 hour, 3 days, 7 days, 14 days or 28 days following the last BrdU injection to allow for discrimination between proliferation and cell survival. Stereologic analysis of the numbers of BrdU-immunoreactive cells in the dentate gyrus by immunohistochemistry and immunofluorescence was performed to assess the number of proliferating dentate granule cells. Colocalization of BrdU immunoreactivity with an immunoreaction for either the neuronal cell marker, NeuN, or astrocytic marker, GFAP, was investigated to determine the phenotype of newborn cells. In both strains, we found adult hippocampal neurogenesis and identified strain differences in proliferation. While numerous BrdU immunoreactive cells were detected in the dentate gyrus in both strains of animals, stereologic analysis of the numbers of BrdU-immunoreactive cells revealed a strain difference with significantly higher cell proliferation and net neurogenesis in C57BL/6 mice. Qualitatively, the appearance and general distribution of BrdU-labeled cells did not differ between the strains. In addition, no strain differences were observed in the relative ratio of neurogenesis versus gliogenesis. The number of BrdU-labeled cells 28 days after the last injection of BrdU was used to estimate the survival of newborn cells in the dentate gyrus. Regardless of strain, the number of BrdU-positive cells at 28 days after injection was similar. These results suggest that genetic background can influence proliferative activity in the adult hippocampus. While results from this study imply that genetic factors that are presumably divergent between the two strains can modify the neurogenic response, it is, as yet, unclear which genes are responsible for regulating this response. Future studies will address cellular and genetic mechanisms that may contribute to strain-dependent differences in the neurogenic program. An understanding of the role of cellular proliferation as it relates to the development and maintenance of epilepsy may provide novel avenues for therapeutic interventions. (Supported by NIH grant NS04763 to PES.)