This study demonstrates three key findings relevant to the identification of receptors regulating neurogenesis: first, newborn cells in the adult dentate gyrus, labeling with either neuronal or glial markers, express p75NTR during early stages of proliferation; second, the number of SGZ newborn cells is significantly reduced in p75NTR (-/-) mice; and third, the numbers of cells in all three categories, those expressing neuronal, glial or neither marker, are significantly reduced in p75NTR (-/-) mice.
The 59% decrease in the number of newborn SGZ cells in p75NTR (-/-) mice found here is similar to the findings of Catts et al., using a 36 hour BrdU oral labeling regime and a 2-week chase period , thereby further supporting a role of p75NTR in dentate progenitor proliferation. The prior study also found a 50-60% reduction in the number of BrdU- NeuN-positive cells at the 2-week time point while the present study detected a 35% decrease in the number of BrdU- NeuN-positive cells at the 1 day time point following the 6-day BrdU labeling protocol. Hence, our study further supports a role for p75NTR in neurogenesis. This effect could be caused by p75NTR promoting survival and/or differentiation of cells undergoing neuronal differentiation. In contrast to the Catts et al study, we found no decrease in dentate gyrus volume. A lack of effect on dentate volume has also been noted in other studies in which SGZ progenitor proliferation and/or neurogenesis is altered [29–31]. In addition to the difference in time points examined, the prior study applied an oral BrdU dose of 650 mg/kg/day compared to the present IP dose of 50 mg/kg/day. While a number of factors are likely to contribute to the difference in findings in terms of dentate volume loss between the studies, it is of interest to note that high BrdU concentrations have been associated with neuronal death .
In addition to the effect of p75NTR on neuron formation, a related critical question is its role in the genesis of non-neuronal cells. In the present study, the GFAP glial maker was applied and revealed that in p75NTR(-/-) mice, there were 60% and 64% decreases in the total number of newborn cell labeled with GFAP or neither marker, respectively. Thus, in p75NTR(-/-) mice the proportion of newborn cells expressing the NeuN marker is increased while the proportion without this marker is decreased. These studies introduce the important concept that while p75NTR appears to contribute to neurogenesis, it might make an even greater contribution to formation of various populations of non-neuronal cells. Thus p75NTR cannot be linked specifically to neurogenesis, but instead appears to play a broader role in dentate cell genesis.
The identification of a role for p75NTR in dentate gyrus progenitor cell production is consistent with the emerging picture of p75NTR regulating cell cycle mechanisms as well as regulating the proliferation and/or differentiation of progenitors or embryonic stem cells in cell culture models and in the SVZ in vivo [16–18, 22]. These findings are also consistent with other studies in p75NTR (-/-) mice in which a greater number of sympathetic neurons are present in early development while at later stages a decrease in the number of mature sympathetic neurons was found, suggesting that during development, p75NTR might first induce proliferation and later apoptosis [12, 33, 34]. Similarly, during embryonic development, p75NTR appears to participate in the early stages of hippocampal cell proliferation, but at later stages induces death of neurons during maturation [12, 35]; and finally at the adult stage is expressed at low levels [11, 33, 36].
While alterations of intrinsic signaling mechanisms in p75NTR (-/-) progenitors are likely to account for the decrease in neurogenesis observed here, it is also possible that factors extrinsic to progenitor cells contribute. For example, lesions in the entorhinal cortex, hippocampal CA1 and CA3 subregions or dentate gyrus induce an increase in dentate neurogenesis [37–40]. Decreased cholinergic input into the dentate gyrus has also been associated with decreased neurogenesis . Interestingly, the p75NTR (-/-) mice used in the present study and other strains carrying the same mutation were shown to have increased dentate cholinergic innervation [42, 43]. Thus, the p75NTR (-/-) mice employed here would be expected to have increased, rather than decreased, neurogenesis if the extrinsic factor of cholinergic innervation played a predominant role.
Studies demonstrating age-related impairments in hippocampal neurogenesis along with recent work showing that brain proNGF levels increase with age  raise the possibility that proNGF might contribute to loss of newborn cells through its interaction with p75NTR. Recently developed p75NTR small molecule ligands are able to promote pro-survival signaling and are also able to prevent proNGF-induced death . Findings in the present study will encourage studies to establish whether p75NTR small molecule ligands can modulate dentate gyrus cell production.