Abstracts

Rationale: Neurogenesis persists throughout life in restricted regions of the mammalian brain and increases after seizures and other forms of brain injury, yet little is known about the function of adult-born neurons in normal or disease states. Several studies support a role for adult dentate granule cell (DGC) neurogenesis in learning and memory by showing deficits after eliminating DGC precursors. Existing evidence also suggests that adult-born DGCs contribute to epilepsy development in rodent models of mTLE. However, many of these studies are confounded by use of irradiation or anti-mitotic agents that may cause deleterious effects. To avoid these potential confounds, we developed a transgenic approach to eliminate neural progenitors and determine the function of adult-born neurons in the intact and injured brain.Methods: Transgenic mice (Nestin-tk) were generated in which the intermediate filament protein, nestin, directs neural progenitor-specific expression of the suicide gene, herpes simplex virus thymidine kinase (HSV-tk). In hemizygous mice, dividing neural progenitors were ablated selectively by intracerebroventricular infusion of the antiviral agent, ganciclovir (GCV), for 7-28 days. Nestin-tk + GCV and three control groups (nestin-tk + vehicle; wild type + GCV; and wild-type + vehicle) were examined. Animals were killed at the end of the GCV infusion except for additional groups (Nestin-tk or wild type + GCV) that survived for 6 weeks after a 28-day treatment. Suppression of neurogenesis was examined by immunostaining for proliferating cells and immature neurons. After 28 day GCV treatment, hippocampal slices were examined for perforant path-DGC long-term potentiation (LTP) and for dentate extracellular field potentials in response to perforant path stimulation at increasing current strength.Results: Animals expressing the nestin-tk gene, but not littermate controls, showed impaired DGC LTP following 28-day GCV treatment. GCV-treated nestin-tk+ animals also showed a decreased input-output curve for EPSP slope after perforant path stimulation compared to controls. Histology showed that neurogenesis was markedly reduced after 7 days of GCV and nearly completely abolished after 28 days; neurogenesis remained suppressed even after a 6-week recovery.Conclusions: These findings suggest that GCV treatment leads to a long-lived suppression of adult neurogenesis in nestin-tk mice. Loss of neurogenesis over a 4-week period impairs hippocampal synaptic plasticity and suggests a role for adult neurogenesis in hippocampus-dependent learning. (Supported by the Epilepsy Foundation of America)