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

Abstract

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.

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…Neither is COMT the only autosomal gene for which sexually dimorphic genetic associations with psychiatric phenotypes have been reported; eg HTR2A with OCD in women (Enoch et al, 2001), MTHFR with schizophrenia in men (Sazci et al, 2005;Kempisty et al, 2006), and ACVII with depression in women (Hines et al, 2006). However, the data do appear more extensive, and in places statistically more convincing, for COMT than for any other autosomal gene we could determine, especially as the findings are complemented by the sexual dimorphism in COMT activity and by a plausible, if incomplete, mechanistic explanation in terms of estrogenic regulation.…”

Neurotoxic Consequences of Chronic Alcohol Withdrawal: Expression Profiling Reveals Importance of Gender Over Withdrawal Severity

“…Figure 2b shows a cluster of genes that were upregulated by EtOH in females. Of interest in this cluster is Adcy7 (adenylyl cyclase type 7), which is associated with alcoholism in humans and sex-specific depression in transgenic and knockout mice (Hines et al, 2006). Acvrl1 (Alk1) is downregulated in females (Figure 2c).…”

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

“…Mice with knock-out of either Gna13 (G␣ 13 ) or Adcy7 (AC7) have been generated (24,25). To determine the involvement of G 13 and AC7 in the regulation of cAMP response by the S1P FIGURE 2.…”

“…Unfortunately G␣ 13 knock-out animals die during early embryogenesis (25). Although the majority of AC7-deficient animals are also embryonic lethal, ϳ6% of AC7 Ϫ/Ϫ mice do survive to adulthood (24) 4 and this leaky phenotype provided an opportunity to examine the role of AC7 in BMDM cells. As shown in Fig.…”