Abstracts

Granule cell progenitors in the dentate gyrus of the hippocampal formation have the unusual capacity to be able to divide in the brains of adult rodents, primates and humans. While the basal proliferation rate of granule cell progenitors in the adult is low compared with development, many studies have shown that dentate granule cell neurogenesis is increased in rodent models of acute seizures and following limbic epileptogenesis. However, it remains unclear what cellular and molecular events trigger neurogenesis and gliogenesis. We sought to determine whether strain-dependent differences in vulnerability to seizure-induced cell death can result in differential regulation of neurogenesis within the hippocampus. Temporal lobe epilepsy with and without hippocampal sclerosis was modeled in young adult male C57BL/6 and FVB/N mice using systemic administration of kainate. Mice were given two daily BrdU injections, 6 hours apart, 3, 7 and 14 days following kainate administration. We investigated changes in cell proliferation of dentate granule cells 3, 7, and 14 days later using the bromodeoxyuridine (BrdU) labeling method. The phenotypic fate and migration of surviving cells (28 days following BrdU administration) was evaluated by stereological analysis of the numbers of BrdU-immunoreactive in the dentate gyrus by immunohistochemistry and colocalization of BrdU immunoreactivity with antibodies against DCX (immature neuronal marker), NeuN (mature neuronal marker), or GFAP (astroglial marker). The number of BrdU-positive cells in the dentate gyrus of both strains was significantly increased compared to control mice on days 3 and 7. Stereologic analysis of the numbers of BrdU-immunoreactive cells revealed a strain difference with significantly less net neurogenesis in C57BL/6 mice 7 days following kainate administration as compared to FVB/N mice. Furthermore, increased survival of newly proliferating cells in the dentate gyrus was observed in C57BL/6 mice as compared to FVB/N mice. Qualitatively, virtually all of the BrdU positive cells, irrespective of mouse strain, were double-labelled with the marker for neuron-specific nuclear protein (NeuN). However, FVB/N mice that underwent status epilepticus displayed aberrantly located BrdU/NeuN-positive cells in the dentate hilus, which was rarely observed in C57BL/6 mice that underwent status epilepticus or in control mice of either strain. These results suggest that increased neurogenesis appears to be a general response to seizure activity, as we found no strain difference in net neurogenesis. However, cell survival appears to be enhanced in those animals (C57BL/6) that do not exhibit hippocampal sclerosis, leading to an increased number of NeuN-immunoreactive neurons being maintained. Modulation of survival by increases in seizure activity alone would suggest that increased seizure activity results in the activation of specific genetic programs that are not associated with subsequent cell death. (Supported by NS047623.)