Archival Report| Volume 71, ISSUE 7, P627-632, April 01, 2012

Adenylate Cyclase 7 Is Implicated in the Biology of Depression and Modulation of Affective Neural Circuitry


      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 knockout mouse, 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 genes 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 polymerase chain reaction, 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.


      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 major depressive disorder and other affective disorders.

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        • Hariri A.R.
        Genetic polymorphisms: A cornerstone of translational biobehavioral research.
        Sci Transl Med. 2010; 2 (18ps16)
        • Pezawas L.
        • Meyer-Lindenberg A.
        • Drabant E.M.
        • Verchinski B.A.
        • Munoz K.E.
        • Kolachana B.S.
        • et al.
        5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression.
        Nat Neurosci. 2005; 8: 828-834
        • Seminowicz D.A.
        • Mayberg H.S.
        • McIntosh A.R.
        • Goldapple K.
        • Kennedy S.
        • Segal Z.
        • Rafi-Tari S.
        Limbic-frontal circuitry in major depression: A path modeling metanalysis.
        Neuroimage. 2004; 22: 409-418
        • Drevets W.C.
        • Price J.L.
        • Simpson Jr, J.R.
        • Todd R.D.
        • Reich T.
        • Vannier M.
        • et al.
        Subgenual prefrontal cortex abnormalities in mood disorders.
        Nature. 1997; 386: 824-827
        • Mayberg H.S.
        • Liotti M.
        • Brannan S.K.
        • McGinnis S.
        • Mahurin R.K.
        • Jerabek P.A.
        • et al.
        Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness.
        Am J Psychiatry. 1999; 156: 675-682
        • Botteron K.N.
        • Raichle M.E.
        • Drevets W.C.
        • Heath A.C.
        • Todd R.D.
        Volumetric reduction in left subgenual prefrontal cortex in early onset depression.
        Biol Psychiatry. 2002; 51: 342-344
        • Drevets W.C.
        • Bogers W.
        • Raichle M.E.
        Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.
        Eur Neuropsychopharmacol. 2002; 12: 527-544
        • Cotter D.
        • Mackay D.
        • Landau S.
        • Kerwin R.
        • Everall I.
        Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder.
        Arch Gen Psychiatry. 2001; 58: 545-553
        • Ongur D.
        • Drevets W.C.
        • Price J.L.
        Glial reduction in the subgenual prefrontal cortex in mood disorders.
        Proc Natl Acad Sci U S A. 1998; 95: 13290-13295
        • Bowley M.P.
        • Drevets W.C.
        • Ongur D.
        • Price J.L.
        Low glial numbers in the amygdala in major depressive disorder.
        Biol Psychiatry. 2002; 52: 404-412
        • Hamidi M.
        • Drevets W.C.
        • Price J.L.
        Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes.
        Biol Psychiatry. 2004; 55: 563-569
        • Sheline Y.I.
        • Barch D.M.
        • Donnelly J.M.
        • Ollinger J.M.
        • Snyder A.Z.
        • Mintun M.A.
        Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study.
        Biol Psychiatry. 2001; 50: 651-658
        • Siegle G.J.
        • Steinhauer S.R.
        • Thase M.E.
        • Stenger V.A.
        • Carter C.S.
        Can't shake that feeling: Event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals.
        Biol Psychiatry. 2002; 51: 693-707
        • Siegle G.J.
        • Thompson W.
        • Carter C.S.
        • Steinhauer S.R.
        • Thase M.E.
        Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: Related and independent features.
        Biol Psychiatry. 2007; 61: 198-209
        • Roberson-Nay R.
        • McClure E.B.
        • Monk C.S.
        • Nelson E.E.
        • Guyer A.E.
        • Fromm S.J.
        • et al.
        Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An fMRI study.
        Biol Psychiatry. 2006; 60: 966-973
        • Sibille E.
        • Wang Y.
        • Joeyen-Waldorf J.
        • Gaiteri C.
        • Surget A.
        • Oh S.
        • et al.
        A molecular signature of depression in the amygdala.
        Am J Psychiatry. 2009; 166: 1011-1024
        • Belmaker R.H.
        • Agam G.
        Major depressive disorder.
        N Engl J Med. 2008; 358: 55-68
        • Caspi A.
        • Sugden K.
        • Moffitt T.E.
        • Taylor A.
        • Craig I.W.
        • Harrington H.
        • et al.
        Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.
        Science. 2003; 301: 386-389
        • Lira A.
        • Zhou M.
        • Castanon N.
        • Ansorge M.
        • Gordon J.
        • Francis J.
        • et al.
        Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter deficient mice.
        Biol Psychiatry. 2003; 54: 960-971
        • Holmes A.
        • Lit Q.
        • Murphy D.L.
        • Gold E.
        • Crawley J.N.
        Abnormal anxiety-related behavior in serotonin transporter null mutant mice: The influence of genetic background.
        Genes Brain Behav. 2003; 2: 365-380
        • Ansorge M.S.
        • Zhou M.
        • Lira A.
        • Hen R.
        • Gingrich J.A.
        Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.
        Science. 2004; 306: 879-881
        • Gross C.
        • Hen R.
        The developmental origins of anxiety.
        Nat Rev Neurosci. 2004; 5: 545-552
        • Sibille E.
        • Lewis D.A.
        SERT-ainly involved in depression, but when?.
        Am J Psychiatry. 2006; 163: 8-11
        • Bengel D.
        • Murphy D.L.
        • Andrews A.M.
        • Wichems C.H.
        • Feltner D.
        • Heils A.
        • et al.
        Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice.
        Mol Pharmacol. 1998; 53: 649-655
        • Paxinos G.
        • Franklin K.B.J.
        The Mouse Brain in Stereotoxic Coordinates.
        Academic Press, San Diego2001
        • Surget A.
        • Wang Y.
        • Leman S.
        • Ibarguen-Vargas Y.
        • Edgar N.
        • Griebel G.
        • et al.
        Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal.
        Neuropsychopharmacology. 2009; 34: 1363-1380
        • Irizarry R.A.
        • Bolstad B.M.
        • Collin F.
        • Cope L.M.
        • Hobbs B.
        • Speed T.P.
        Summaries of Affymetrix GeneChip probe level data.
        Nucleic Acids Res. 2003; 31: e15
        • Brown S.M.
        • Peet E.
        • Manuck S.B.
        • Williamson D.E.
        • Dahl R.E.
        • Ferrell R.E.
        • Hariri A.R.
        A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity.
        Mol Psychiatry. 2005; 10 (805): 884-888
        • Brown S.M.
        • Manuck S.B.
        • Flory J.D.
        • Hariri A.R.
        Neural basis of individual differences in impulsivity: Contributions of corticolimbic circuits for behavioral arousal and control.
        Emotion. 2006; 6: 239-245
        • Manuck S.B.
        • Brown S.M.
        • Forbes E.E.
        • Hariri A.R.
        Temporal stability of individual differences in amygdala reactivity.
        Am J Psychiatry. 2007; 164: 1613-1614
        • Hines L.M.
        • Hoffman P.L.
        • Bhave S.
        • Saba L.
        • Kaiser A.
        • Snell L.
        • et al.
        A sex-specific role of type VII adenylyl cyclase in depression.
        J Neurosci. 2006; 26: 12609-12619
        • Hariri A.R.
        The neurobiology of individual differences in complex behavioral traits.
        Annu Rev Neurosci. 2009; 32: 225-247
        • Phillips M.L.
        • Drevets W.C.
        • Rauch S.L.
        • Lane R.
        Neurobiology of emotion perception II: Implications for major psychiatric disorders.
        Biol Psychiatry. 2003; 54: 515-528
        • Desrivieres S.
        • Pronko S.P.
        • Lourdusamy A.
        • Ducci F.
        • Hoffman P.L.
        • Wodarz N.
        • et al.
        Sex-specific role for adenylyl cyclase type 7 in alcohol dependence.
        Biol Psychiatry. 2011; 69: 1100-1108
        • Duman R.S.
        • Heninger G.R.
        • Nestler E.J.
        A molecular and cellular theory of depression.
        Arch Gen Psychiatry. 1997; 54: 597-606
        • McGarry L.M.
        • Packer A.M.
        • Fino E.
        • Nikolenko V.
        • Sippy T.
        • Yuste R.
        Quantitative classification of somatostatin-positive neocortical interneurons identifies three interneuron subtypes.
        Front Neural Circuits. 2010; 4: 12
        • Zhou Z.
        • Zhu G.
        • Hariri A.R.
        • Enoch M.A.
        • Scott D.
        • Sinha R.
        • et al.
        Genetic variation in human NPY expression affects stress response and emotion.
        Nature. 2008; 452: 997-1001
        • Lewis D.A.
        • Gonzalez-Burgos G.
        Pathophysiologically based treatment interventions in schizophrenia.
        Nat Med. 2006; 12: 1016-1022
        • Sosulina L.
        • Graebenitz S.
        • Pape H.C.
        GABAergic interneurons in the mouse lateral amygdala: A classification study.
        J Neurophysiol. 2010; 104: 617-626
        • Pandey G.N.
        • Dwivedi Y.
        • Ren X.
        • Rizavi H.S.
        • Mondal A.C.
        • Shukla P.K.
        • Conley R.R.
        Brain region specific alterations in the protein and mRNA levels of protein kinase A subunits in the post-mortem brain of teenage suicide victims.
        Neuropsychopharmacology. 2005; 30: 1548-1556
        • Hariri A.R.
        • Weinberger D.R.
        Imaging genomics.
        Br Med Bull. 2003; 65: 259-270
        • Caspi A.
        • Hariri A.R.
        • Holmes A.
        • Uher R.
        • Moffitt T.E.
        Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits.
        Am J Psychiatry. 2010; 167: 509-527
        • Munafo M.R.
        • Brown S.M.
        • Hariri A.R.
        Serotonin transporter (5-HTTLPR) genotype and amygdala activation: A meta-analysis.
        Biol Psychiatry. 2008; 63: 852-857
        • Cohen-Woods S.
        • Gaysina D.
        • Craddock N.
        • Farmer A.
        • Gray J.
        • Gunasinghe C.
        • et al.
        Depression Case Control (DeCC) Study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder.
        Hum Mol Genet. 2009; 18: 1504-1509
        • Hemmings S.M.
        • Stein D.J.
        The current status of association studies in obsessive-compulsive disorder.
        Psychiatr Clin North Am. 2006; 29: 411-444
        • Rizig M.A.
        • McQuillin A.
        • Puri V.
        • Choudhury K.
        • Datta S.
        • Thirumalai S.
        • et al.
        Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4).
        Am J Med Genet B Neuropsychiatr Genet. 2006; 141B: 296-300
        • Hasler G.
        • Drevets W.C.
        • Manji H.K.
        • Charney D.S.
        Discovering endophenotypes for major depression.
        Neuropsychopharmacology. 2004; 29: 1765-1781
        • Suslow T.
        • Konrad C.
        • Kugel H.
        • Rumstadt D.
        • Zwitserlood P.
        • Schoning S.
        • et al.
        Automatic mood-congruent amygdala responses to masked facial expressions in major depression.
        Biol Psychiatry. 2010; 67: 155-160
        • Townsend J.D.
        • Eberhart N.K.
        • Bookheimer S.Y.
        • Eisenberger N.I.
        • Foland-Ross L.C.
        • Cook I.A.
        • et al.
        fMRI activation in the amygdala and the orbitofrontal cortex in unmedicated subjects with major depressive disorder.
        Psychiatry Res. 2010; 183: 209-217
        • Monk C.S.
        • Klein R.G.
        • Telzer E.H.
        • Schroth E.A.
        • Mannuzza S.
        • Moulton 3rd, J.L.
        • et al.
        Amygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depression.
        Am J Psychiatry. 2008; 165: 90-98
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        4th ed. American Psychiatric Association, Washington, DC2000 (Text Revision)
        • Fakra E.
        • Hyde L.W.
        • Gorka A.
        • Fisher P.M.
        • Munoz K.E.
        • Kimak M.
        • et al.
        Effects of HTR1A C(−1019)G on amygdala reactivity and trait anxiety.
        Arch Gen Psychiatry. 2009; 66: 33-40
        • Stein M.B.
        • Simmons A.N.
        • Feinstein J.S.
        • Paulus M.P.
        Increased amygdala and insula activation during emotion processing in anxiety-prone subjects.
        Am J Psychiatry. 2007; 164: 318-327
        • Shin L.M.
        • Whalen P.J.
        • Pitman R.K.
        • Bush G.
        • Macklin M.L.
        • Lasko N.B.
        • et al.
        An fMRI study of anterior cingulate function in posttraumatic stress disorder.
        Biol Psychiatry. 2001; 50: 932-942
        • Holmes A.J.
        • Pizzagalli D.A.
        Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder.
        Arch Gen Psychiatry. 2008; 65: 179-188
        • Kaufman J.
        • Charney D.
        Comorbidity of mood and anxiety disorders.
        Depress Anxiety. 2000; 12: 69-76

      Linked Article

      • Transducing Emotionality: The Role of Adenylyl Cyclases
        Biological PsychiatryVol. 71Issue 7
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          Various psychiatric disorders, including depression, anxiety, and other mood disorders, as well as responses to addictive drugs, have been linked to malfunctions of receptors coupled to the cyclic adenosine monophosphate (AMP) second-messenger signaling system and/or malfunction of downstream mediators such as protein kinase A (PKA) and the transcription factor cyclic AMP response element–binding protein. What has generally been largely ignored are the enzymes that generate cyclic AMP, the family of adenylyl cyclases (ACs).
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      • Erratum to: Adenylate Cyclase 7 Is Implicated in the Biology of Depression and Modulation of Affective Neural Circuitry
        Biological PsychiatryVol. 72Issue 2
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          An error has been discovered in “Adenylate Cyclase 7 Is Implicated in the Biology of Depression and Modulation of Affective Neural Circuitry” by Joeyen-Waldorf et al. which appeared in Biological Psychiatry (2012;71:627–632). The authors would like to correct two inaccurate references in the third paragraph of the Discussion (column 2 of page 630). The following text has the correct references. Note that these are new references which are not cited in the original paper:
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