Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder.
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.
de Mooij-van Malsen
Annetrude J G
AJ
Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Centre Utrecht, 3584 CG Utrecht, The Netherlands.
van Lith
Hein A
HA
Oppelaar
Hugo
H
Hendriks
Judith
J
de Wit
Marina
M
Kostrzewa
Elzbieta
E
Breen
Gerome
G
Collier
David A
DA
Olivier
Berend
B
Kas
Martien J
MJ
D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D004924:Escape Reaction / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051659:KCNQ3 Potassium Channel / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D019964:Mood Disorders / Q000235:genetics*; D009043:Motor Activity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*
D051659:KCNQ3 Potassium Channel; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8