Behavioral trait genetics in mice; Opportunities for translational research of psychiatric endophenotypes

Mood disorders have powerful effects on the lives of many people. Finding the mechanisms underlying these disorders is essential to develop selective treatment. In this thesis, interspecies trait genetics are used on behavioural domains to unravel the complex genetics of involved endophenotypes. We developed a home cage environment, allowing automated multi-day recordings, assessing the animals’ reduced preference for exposed areas (avoidance behaviour) independent of motor activity levels. To efficiently screen for genetic loci of interest, we used chromosome substitution strains (CSS) of mice; inbred strains with an A/J chromosome substituting the corresponding chromosome in the C57BL/6J background. Following behavioral testing of the full panel of chromosome substitution strains in the home cage environment, we were able to select particular strains of interest and, by the use of a F2-population, map different genetic loci specific for motor activity levels and avoidance behaviour. We genetically mapped the expression of baseline motor activity levels to mouse chromosome 1. By data mining an existing phenotypic and genotypic data set of genetically heterogeneous mice, we refined the QTL to a 312 kb interval containing a single gene (A830043J08Rik). Genome-wide microarray gene expression profiling showed a significant up-regulation of Epha4 in low active F2-individuals. Neuro-anatomical research in the spinal cord and ventral roots revealed considerable differences in motor neuron morphology, with A/J and CSS1 having smaller, possibly less developed, motor neuron axons. Also, for CSS1 and C57BL/6J, a correlation was found between motor activity levels, uncoordinated hind limb movement and neuro-anatomical differences in the cortico-spinal tract. This thesis also shows that both chromosome 15 and 19 are involved in avoidance behaviour. For chromosome 15, a small genetic region was found associated with this behavior. This QTL proved to be homologous with a human linkage region for bipolar disorder. By combining mouse SNP data with the WTCCC GWA study, 2 genes of interest were identified, showing allele frequency differences between healthy controls and bipolar patients. Only Adcy8 was differentially expressed as a function of mouse avoidance behavior in brain regions associated with mood regulation. Since Adcy8 mutant mice show altered anxiety-related behavior and the functioning of the adenylyl cyclase (AC) system is known to be changed in bipolar patients and is a target for mood stabilizers, we conclude that this gene encodes a behavioral endophenotype of bipolar disorder. Activation of AC causes the conversion of ATP to cAMP, activating (amongst others) protein kinase A (PKA). Interestingly, the QTL on mouse chromosome 19 was also found to be homologous with a human bipolar linkage region and contains genes which are functional in the PKA signaling pathway. If the changes in behavior observed in CSS15 and CSS19 are indeed caused by changes in the AC-cAMP signaling pathway, testing these and other strains in the home cage environment as described in this thesis can provide great opportunities not only to screen for other genes and cascades related to this pathway, but also to use a genetically validated model to search for effective treatment options influencing this biological signaling pathway