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The Journal of Neuroscience, November 29, 2006, 26(48):12609-12619; doi:10.1523/JNEUROSCI.1040-06.2006

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Neurobiology of Disease
A Sex-Specific Role of Type VII Adenylyl Cyclase in Depression

Lisa M. Hines,¹ Paula L. Hoffman,¹ Sanjiv Bhave,¹ Laura Saba,¹ Alan Kaiser,¹ Larry Snell,¹ Igor Goncharov,¹ Lucie LeGault,² Maurice Dongier,² Bridget Grant,³ Sergey Pronko,¹ Larry Martinez,¹ Masami Yoshimura,⁴ Boris Tabakoff,¹ and World Health Organization/International Society for Biomedical Research on Alcoholism Study on State and Trait Markers of Alcohol Use and Dependence Investigators

¹Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, ²Department of Psychiatry, McGill University, Montreal, Quebec, Canada H4H 1R3, ³Division of Epidemiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852, and ⁴Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana 70803

Correspondence should be addressed to Boris Tabakoff, University of Colorado at Denver and Health Sciences Center at Fitzsimons, Department of Pharmacology, Mail Stop F-8303, P.O. Box 6511, Aurora, CO 80045-0511. Email: boris.tabakoff{at}uchsc.edu

Major depression represents a complex mental disorder. The identification of biological markers that define subtypes of major depressive disorder would greatly facilitate appropriate medical treatments, as well as provide insight into etiology. Reduced activity of the cAMP signaling system has been implicated in the etiology of major depression. Previous work has shown low adenylyl cyclase activity in platelets and postmortem brain tissue of depressed individuals. Here, we investigate the role of the brain type VII isoform of adenylyl cyclase (AC7) in the manifestation of depressive symptoms in genetically modified animals, using a combination of in vivo behavioral experiments, gene expression profiling, and bioinformatics. We also completed studies with humans on the association of polymorphisms in the AC7 gene with major depressive illness (unipolar depression) based on Diagnostic and Statistical Manual of Mental Disorders IV criteria. Collectively, our results demonstrate a sex-specific influence of the AC7 gene on a heritable form of depressive illness.

Key words: adenylyl cyclase; association study; depression; haplotype; human; mouse models; genetic polymorphisms

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Received March 9, 2006; revised Oct. 4, 2006; accepted Oct. 21, 2006.

Correspondence should be addressed to Boris Tabakoff, University of Colorado at Denver and Health Sciences Center at Fitzsimons, Department of Pharmacology, Mail Stop F-8303, P.O. Box 6511, Aurora, CO 80045-0511. Email: boris.tabakoff{at}uchsc.edu

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