Natural variation and genetic covariance in adult hippocampal neurogenesis

Abstract

Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB͞BXA, n ‫؍‬ 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1͞CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.gene array ͉ hippocampus ͉ precursor ͉ quantitative trait loci ͉ stem cell N eurogenesis in adult mammals is modulated by complex interactions among genetic and environmental factors. Our goal is to use a systems genetics approach to determine how the development of new neurons and glia is modulated by gene polymorphisms, activity, and environmental stimuli. A first step toward this goal is to analyze natural variation and genetic covariance among key neurogenesis parameters such as proliferation, survival, and differentiation of new cells. We have shown that natural variation is substantial among different strains of mice (1-3). The normal range of variation often exceeds the effects of single gene mutations in engineered lines of mice.In this study, we extended this analysis of normal variation and applied a systems genetics approach to study the covariance structure of four key parameters of adult hippocampal neurogenesis across two large genetic reference populations consisting of a total of 52 recombinant inbred strains. This approach allowed us to exploit covariance of diverse traits to demonstrate biological linkage and pleiotropy (4, 5). The analysis, however, extends beyond a correlative approach. Both of the genetic reference populations used, the BXD and AXB͞BXA sets, are standard mapping panels, making it possible to search for gene loci, so-called quantitative trait loci (QTL), that produce common variation and pleiotropy among traits linked to adult hippocampal neurogenesis.A...

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

“…In the present study, A/J mice exhibited higher baseline new neuron formation than DBA/2J mice, a finding in agreement with previous reports (Kempermann and Gage, 2002;Kempermann et al, 2006). Although it is possible that A/J mice failed to show an increase in hippocampal cell proliferation in response to fluoxetine because of a ceiling effect (eg baseline proliferation is already at maximum), this is an unlikely interpretation: C57BL/6J (B6) mice have been shown to have a higher rate of hippocampal cell proliferation than A/J mice, but, unlike A/J, B6 mice are behaviorally responsive to the antidepressant effects of fluoxetine treatment (Kempermann et al, 1997(Kempermann et al, , 2006Bai et al, 2001;Hayes and Nowakowski, 2002).…”

“…The difference between DBA/2J and A/J is similar to that observed in previous studies, which have shown that A/J mice exhibit a higher rate of hippocampal cell proliferation than DBA/2J mice (Kempermann et al, 2006). In two strains, DBA/2J and 129S1, chronic fluoxetine treatment increased the number of BrdU-positive cells (p ¼ 0.016 and 0.02, respectively).…”

“…Recent studies have shown that inbred mouse strains vary in the rate of adult neuronal proliferation and survival, and in the behavioral response to antidepressant treatment (Lucki et al, 2001;Kempermann et al, 2006). Given the strain-dependent variability in both antidepressant response and neurogenesis, we hypothesized that there might be a genetic component to the effect of fluoxetine on neuronal proliferation.…”

“…The inbred strain model may also be expanded upon to dissect the effect of antidepressants on additional aspects of neurogenesis (Kempermann et al, 2006). Although the present study addressed only neuronal proliferation, there is evidence that antidepressant treatment has an effect on other phases of neurogenesis as well.…”

“…Although it is possible that A/J mice failed to show an increase in hippocampal cell proliferation in response to fluoxetine because of a ceiling effect (eg baseline proliferation is already at maximum), this is an unlikely interpretation: C57BL/6J (B6) mice have been shown to have a higher rate of hippocampal cell proliferation than A/J mice, but, unlike A/J, B6 mice are behaviorally responsive to the antidepressant effects of fluoxetine treatment (Kempermann et al, 1997(Kempermann et al, , 2006Bai et al, 2001;Hayes and Nowakowski, 2002). It is important to note, however, that our data suggest that the rate of baseline hippocampal cell proliferation is not correlated with baseline TST immobility: rather, the correlation between cell proliferation and TST activity is specific to the effect of fluoxetine.…”