Genetic control of adult neurogenesis: interplay of differentiation, proliferation and survival modulates new neurons function, and memory circuits

Abstract

Within the hippocampal circuitry, the basic function of the dentate gyrus is to transform the memory input coming from the enthorinal cortex into sparse and categorized outputs to CA3, in this way separating related memory information. New neurons generated in the dentate gyrus during adulthood appear to facilitate this process, allowing a better separation between closely spaced memories (pattern separation). The evidence underlying this model has been gathered essentially by ablating the newly adult-generated neurons. This approach, however, does not allow monitoring of the integration of new neurons into memory circuits and is likely to set in motion compensatory circuits, possibly leading to an underestimation of the role of new neurons. Here we review the background of the basic function of the hippocampus and of the known properties of new adult-generated neurons. In this context, we analyze the cognitive performance in mouse models generated by us and others, with modified expression of the genes Btg2 (PC3/Tis21), Btg1, Pten, BMP4, etc., where new neurons underwent a change in their differentiation rate or a partial decrease of their proliferation or survival rate rather than ablation. The effects of these modifications are equal or greater than full ablation, suggesting that the architecture of circuits, as it unfolds from the interaction between existing and new neurons, can have a greater functional impact than the sheer number of new neurons. We propose a model which attempts to measure and correlate the set of cellular changes in the process of neurogenesis with the memory function.

Running Rescues Defective Adult Neurogenesis by Shortening the Length of the Cell Cycle of Neural Stem and Progenitor Cells

“…This overproduction of newborn neurons gives rise during adulthood to a severe depletion of stem and progenitor cells, caused by a concomitant decrease of their proliferative capability, accompanied by premature exit from cell cycle and massive apoptosis. The increased exit from cell cycle is probably dependent on an increment of p21 expression to compensate for the loss of the cell cycle regulation exerted by Btg1 . These data strongly suggest that Btg1 plays an essential role in the physiological maintenance of the neurogenic pool and in the proper control of adult neurogenesis, as also implied by its expression in the adult and developing SVZ and DG (; Supporting Information Fig.…”

“…Further work will be useful to understand the molecular mechanisms of Btg1 in maintaining NSC quiescence and the interactions with other pathways. These may also include another Btg family‐related gene, Tis21/Btg2, which appears to be required for terminal differentiation of the DG progenitor cells , and thus could play a role in sustaining the expansion of NSC throughout the exercise‐induced neurogenesis.…”

Hydroxytyrosol stimulates neurogenesis in aged dentate gyrus by enhancing stem and progenitor cell proliferation and neuron survival

“…12,13 The new dentate gyrus neurons play a key role in memory coding, as they are more excitable up to the age of 4 weeks, thus improving the resolution and correlation between new memories and old memories of events encoded by mature neurons. 3,14,15 Therefore, adult hippocampal neurogenesis contributes to cognition. 16 Remarkably, during aging the generation of progenitor cells and neurons in the dentate gyrus and SVZ undergoes a progressive decrease.…”

Control of the Normal and Pathological Development of Neural Stem and Progenitor Cells by the PC3/Tis21/Btg2 and Btg1 Genes

“…If, on the contrary, PC3/Tis21 is ablated, the ensuing impairment of terminal differentiation of dentate gyrus neurons is associated to a selective loss of associative memory (Farioli‐Vecchioli et al, ), while the impaired differentiation of the SVZ/olfactory bulb neurons is associated to a loss of olfactory discrimination (Farioli‐Vecchioli et al, ). Clearly, these findings point to to a general paradigm, i.e., how the timing of differentiation of a neuron is extremely critical for its function (for discussion, Tirone et al, ).…”