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

de Mooij-van Malsen, Annetrude (J.G.); van Lith, Hein A.; Oppelaar, Hugo; Hendriks, Judith; de Wit, Marina; Kostrzewa, Elżbieta; Breen, Gerome; Collier, David A.; Olivier, Berend; Kas, Martien J.

doi:10.1016/j.biopsych.2009.06.016

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

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

Annetrude (J.G.) de Mooij-van Malsen
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
Hein A. van Lith
- Faculty of Veterinary Medicine, Department of Animals, Science, Society, Division of Laboratory Animal Science, Utrecht University, Utrecht, The Netherlands
Hugo Oppelaar
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
Judith Hendriks
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
Marina de Wit
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
Elżbieta Kostrzewa
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
Gerome Breen
- Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, United Kingdom
David A. Collier
- Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, United Kingdom
Berend Olivier
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Utrecht Institute for Pharmaceutical Sciences, Department of Psychopharmacology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
Martien J. Kas
- Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Address correspondence to Martien Kas, Ph.D., Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands

Received 2 April 2009; received in revised form 18 June 2009; accepted 21 June 2009. published online 20 August 2009.

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.