Further work will be needed to substantiate and extend this hypothesis. response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research. gene that leads to a substitution of arginine to proline at position 447 and a significant decrease in brain serotonin levels (Zhang et al., 2004) (for genomic location of this and other mouse genes discussed in this article, see Fig. 2). The BALB/cJ and DBA/2J inbred mouse strains that carry the 1473G allele exhibit significantly lower levels of serotonin in the frontal cortex and striatum SPRY4 relative to the C57BL/6J and 129X1/SvJ strains (with 1473C) (Zhang et al., 2004) (see also Hackler et al., 2006). Interestingly, the BALB/cJ and DBA/2J strains also tend to exhibit higher levels of anxiety-like behavior and stress-reactivity than C57BL/6J, and BALB/cJ also show greater sensitivity to the antidepressant-like effects of SRI’s Metixene hydrochloride hydrate (Anisman et al., 2001; Belzung and Griebel, 2001; Dulawa et al., 2004). The implication here is that the low functioning mouse variant could account for the abnormal anxiety- and stress-related phenotype of these and possibly other mouse strains (Zhang et al., 2004). Further work will be needed to substantiate and extend this hypothesis. For example, because Tph2-mediated serotonin synthesis is known to be regulated by glucocorticoids in C57BL/6J (Clark et al., 2007; Clark et al., 2005) it would be of interest to examine whether this mechanism is impaired in strains with the low-expressing SNP such as DBA/2J and BALB/cJ (Table 1). Open in a separate window Fig. 2 Approximate genomic location of serotonin system genes implicated in stress-related phenotypes in the murine genome. = 5-HT1A receptor (13 58.0 centimorgans (cM)), = 5-HT1B receptor (9 46.0 cM), = 5-HT2A receptor (14 41.5 cM), = 5-HT2C receptor (X 66.15 cM), = 5-HT3A receptor (19 A5.3), = 5-HT4 receptor (18 D3), = 5-HT5A receptor (5 15.0 cM), = 5-HT6 receptor (4 64.9 cM), = 5-HT7 receptor (19 33.0 cM), = monoamine oxidase A (X 5.2 cM), = serotonin transporter (11 42.0 cM), = vesicular monoamine transporter 2 (19 D3), = tryptophan hydroxylase 1 (7 23.5 cM), Metixene hydrochloride hydrate = tryptophan hydroxylase 2 (10 D2). Table 1 Summary of stress-related phenotypes associated with experimentally induced mouse gene mutations and naturally occurring variation in mouse and man in QTL associated with antidepressant efficacyC= 5-HT1A receptor; = 5-HT2A receptor; = 5-HT2C receptor; = 5-HT3A receptor; = 5-HT4 receptor; = 5-HT5A receptor; = 5-HT6 receptor; = 5-HT7 receptor; KO = knockout; = monoamine oxidase A; QTL = quantitative trait locus; = serotonin transporter; = vesicular monoamine transporter 2 Metixene hydrochloride hydrate (Vmat2); = tryptophan hydroxylase 1; = tryptophan hydroxylase 2. Whether genetic control of human might affect human stress-related disease has generated a lot of interest. A loss-of-function SNP (G1463A) in the human gene has been associated with increased incidence of depression; although it is not yet clear whether this association extends beyond a certain subpopulation of patients (Delorme et al., 2006; Zhang et al., 2006; Metixene hydrochloride hydrate Zill et al., 2004). In addition, using functional magnetic resonance imaging (fMRI) Hariri and colleagues have recently shown that a more common SNP (G(?844)T) in the promoter region of the gene predicts exaggerated amygdala responses to threatening faces (Brown et al., 2005). Finally, there is preliminary evidence that a 218A/C polymorphism is also linked to increased rates of anxiety disorders and depressive illness (Christiansen et al., 2007). Taken together, these data provide encouraging support for the notion that genetic variation in the control of serotonin synthesis, via Tph2, can affect stress-related behaviors and the neural systems supporting these behaviors, both in mouse and in man. Although present to some extent in the rodent DRN (Gundlah et al., 2005), the tryptophan hydroxylase isoform Tph1 largely governs peripheral serotonin synthesis. However, even if Tph1 did not act directly in the brain (which is still not certain), the porous bloodCbrain barrier in developing rodents could render the developing brain highly sensitive to the effects of variation in Tph1 gene function during ontogeny. Intriguingly in this context, mouse dams in which the gene is knocked out produce offspring that exhibit gross abnormalities in brain development, regardless of the offspring’s own genotype (Cote et al., 2007). This demonstrates that loss of the maternal supply of peripheral serotonin can have profound consequences for the brain. The question of whether gene variation in the human or mouse gene impacts the development of corticolimbic circuits mediating stress responses has not yet been answered, but represents an important avenue for future work. It.