Interspecies Trait Genetics Reveals Association of Adcy8 with Mouse Avoidance Behavior and a Human Mood Disorder

doi:10.1016/j.biopsych.2009.06.016

Biological Psychiatry

Volume 66, Issue 12, 15 December 2009, Pages 1123-1130

https://doi.org/10.1016/j.biopsych.2009.06.016 Get rights and content

Background

Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior.

Methods

In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder.

Results

We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior.

Conclusions

Our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.

Section snippets

CSSs

The CSS panel (C57BL/6J-Chr; 1^A/NaJ to C57BL/6J-Chr; 19^A/NaJ, C57BL/6J-Chr; X^A/NaJ, C57BL/6J-Chr; Y^A/NaJ; henceforth referred to as CSS1, CSS2, and so forth) was studied (except for CSS7 due to low availability). See Supplement 1 for further information on amount of mice tested, the generation of the F₂-population, and housing conditions.

Mouse Behavioral Testing

All experimental procedures were approved by the ethical committee for animal experimentation of the University Medical Center Utrecht, The Netherlands.

Genetic Dissection of Mouse Avoidance Behavior

To efficiently screen for genetic regions influencing motor activity levels or avoidance behavior, the CSS mouse panel, their genetic background strains (C57BL/6J host, A/J donor strain), and a F₂-progeny for QTL mapping were tested in an automated home cage environment for 3 continuous days. In the automated home cage environment (Figure 1A–1C) the animals can choose to eat at two different feeding platforms, where they had ad libitum access to regular chow. At one feeding platform the animals

Discussion

Understanding the pathophysiology of affective disorders, thus identifying underlying disease pathways and hence identifying novel drug targets, is crucial for the development of selective treatments. One approach to this is the mapping of susceptibility genes that influence behavioral endophenotypes of the disorder, because they might identify treatable components of the disease. Thus, endophenotypes that can be examined across species not only provide tools for mapping genes and therefore

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Archival ReportInterspecies Trait Genetics Reveals Association of Adcy8 with Mouse Avoidance Behavior and a Human Mood Disorder

Background

Methods

Results

Conclusions

Section snippets

CSSs

Mouse Behavioral Testing

Genetic Dissection of Mouse Avoidance Behavior

Discussion

Eur J Pharmacol

Trends Neurosci

Behav Proc

Peptides

Curr Biol

Am J Hum Genet