|Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology. Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter (SERT) knock-out mouse (SERTKO), a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans, was conducted to identify gene with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples. Comparative analysis identified genes with conserved transcript changes in amygdala (n=29) and cingulate cortex (n=19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative PCR, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity (Figure). This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to MDD and other affective disorders.
|Joeyen-Waldorf J, Nikolova Y, Edgar E, Walsh C, Kota R, Lewis DA, Ferrell R, Manuck SB, Hariri AR, Sibille E: Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry. Biol Psychiatry, ePub January 20, 2012.