It is now well established that neurogenesis in the rodent subgranular zone of the hippocampal dentate gyrus continues throughout adulthood. Neuroblasts born in the dentate subgranular zone migrate into the granule cell layer, where they differentiate into neurons known as dentate granule cells. Suppression of neurogenesis by irradiation or genetic ablation has been shown to disrupt synaptic plasticity in the dentate gyrus and impair some forms of hippocampus-dependent learning and memory. Using a recently developed transgenic mouse model for suppressing neurogenesis, we sought to determine the long-term impact of ablating neurogenesis on synaptic plasticity in young-adult mice. Consistent with previous reports, we found that ablation of neurogenesis resulted in significant deficits in dentate gyrus long-term potentiation (LTP) when examined at a time proximal to the ablation. However, the observed deficits in LTP were not permanent. LTP in the dentate gyrus was restored within 6 wk and this recovery occurred in the complete absence of neurogenesis. The recovery in LTP was accompanied by prominent changes within the dentate gyrus, including an increase in the survival rate of newborn cells that were proliferating just before the ablation and a reduction in inhibitory input to the granule cells of the dentate gyrus. These findings suggest that prolonged suppression of neurogenesis in young-adult mice results in wide-ranging compensatory changes in the structure and dynamics of the dentate gyrus that function to restore plasticity.adult neurogenesis | thymidine kinase | metaplasticity | miniature inhibitory postsynaptic currents F orebrain neurogenesis persists into adulthood in the subgranular zone (SGZ) of the hippocampal dentate gyrus in rodents (1-4). Under normal conditions (i.e., in the absence of overt pathology) neuroblasts that arise in the SGZ migrate a short distance into the dentate granule cell layer (GCL) and differentiate into dentate granule cells (DGCs), where they subsequently reach functional maturity (5, 6). The birth, integration, and survival of DGCs are modulated by environmental enrichment (7), exercise (8), stress (9, 10), hippocampus-dependent learning (11), and direct manipulation of neuronal activity (12, 13). In addition, adult-born DGCs respond preferentially in hippocampus-dependent memory tasks (14) and display increased synaptic plasticity relative to mature DGCs (15,16).The correlation of increased DGC neurogenesis with cognitively demanding tasks has led to the hypothesis that adult-born neurons are integral participants in hippocampus-dependent memory processing and behavior. The role of adult-born DGCs in hippocampal function has been studied at the behavioral level in rodents after suppressing neurogenesis with antimitotic agents (17, 18), radiation (19), or genetic targeting (19)(20)(21)(22). These studies indicate that adult-born DGCs are necessary for some hippocampus-dependent tasks, although results have been inconsistent and vary by rodent species and strain, behavioral ...

Trains of action potentials in CA1 pyramidal neurons are followed by a prolonged calciumdependent post-burst afterhyperpolarization (AHP) that serves to limit further firing to a sustained depolarizing input. A reduction in the AHP accompanies acquisition of several types of learning and increases in the AHP are correlated with age-related cognitive impairment. The AHP develops primarily as the result of activation of outward calcium-activated potassium currents; however the precise source of calcium for activation of the AHP remains unclear. There is substantial experimental evidence suggesting that calcium influx via voltage-gated L-type calcium channels (L-VGCCs) contributes to the generation of the AHP. Two L-VGCC subtypes are predominately expressed in the hippocampus, Ca V 1.2 and Ca V 1.3, however it is not known which L-VGCC subtype is involved in generation of the AHP. This ambiguity is due in large part to the fact that at present there are no subunit-specific agonists or antagonists. Therefore, using mice in which the gene encoding Ca V 1.2 or Ca V 1.3 was deleted, we sought to determine the impact of alterations in levels of these two L-VCGG subtypes on neuronal excitability. No differences in any AHP measure were seen between neurons from Ca V 1.2 knockout mice and controls. However, the total area of the AHP was significantly smaller in neurons from Ca V 1.3 knockout mice as compared to neurons from wildtype controls. A significant reduction in the amplitude of the AHP was also seen at the 1 sec time point in neurons from Ca V 1.3 knockout mice as compared to those from controls. Reductions in both the area and 1 sec amplitude suggest the involvement of calcium influx via Ca V 1.3 in the slow AHP (sAHP). Thus, the results of our study demonstrate that deletion of Ca V 1.3, but not Ca V 1.2, significantly impacts the generation of the sAHP.