Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice.

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.

Deletion of the L-type calcium channel Ca(V) 1.3 but not Ca(V) 1.2 results in a diminished sAHP in mouse CA1 pyramidal neurons.

Trains of action potentials in CA1 pyramidal neurons are followed by a prolonged calcium-dependent postburst 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 with neurons from wild-type controls. A significant reduction in the amplitude of the AHP was also seen at the 1 s time point in neurons from Ca(V) 1.3 knockout mice as compared with those from controls. Reductions in both the area and 1 s 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.