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

Abstract

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 ...

Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus

“…These data indicate that absence of NFATc4 affects the threshold for plasticity induction in the DG when inhibition is intact. They also are in agreement with previous studies showing that a reduction in the number of DG adult-born neurons (35)(36)(37)(38), which have a lower threshold for LTP induction than mature ones (39), results in similar impaired LTP formation.…”

Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

“…Significant alteration of neurogenesis could be one of the contributing factors to diminished plasticity in DS. Interestingly, studies involving mice to different enrichments or pharmacotherapies enhanced both neurogenesis and learning (Deng et al, 2010;Mongiat & Schinder, 2011;Saxe et al, 2006;Shors et al, 2002;Singer at al., 2011), including Ts65Dn mice (Bianchi et al, 2010). Moreover, manipulations that stimulate adult neurogenesis in mice also increase LTP (van Praag et al, 1999).…”

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

“…Another confound to consider when ablating adult neurogenesis was highlighted by Singer et al (2011) who found that although PP LTP was absent 4 wk after ablation (see "Adult hippocampal neurogenesis and its regulation") it returned to control levels by 10-wk post-ablation. To account for this recovery, they showed that GABAergic innervation of matGCs decreases over time following ablation, suggestive of a chronic homeostatic/pathological change to the DG network.…”

“…Given that this is typically a chronic manipulation, such studies must consider if the animal may be able to employ alternative strategies to function in the experimental paradigm, if compensatory mechanisms might lessen the impact of ablating adult neurogenesis (e.g., Singer et al 2011), or if there is redundancy in the abGC population when ablation is incomplete. Conversely, false positive results may arise if there are sideeffects associated with the ablation technique (see Box 4).…”