Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice

The forced swim test (FST) and tail suspension test (TST) are widely used and well established screening paradigms for antidepressants. A variety of antidepressive agents are known to reduce immobility time in both FST and TST. To identify genetic determinants of immobility duration in both tests, we analyzed 560 F2 mice from an intercross between C57BL/6 (B6) and C3H/He (C3) strains. Composite interval mapping revealed five major loci (suggestive and significant linkage) affecting immobility in the FST, and four loci for the TST. The quantitative trait loci (QTL) on chromosomes 8 and 11 overlap between the two behavioral measures. Genome-wide interaction analysis, which was developed to identify locus pairs that may contribute epistatically to a phenotype, detected two pairs of chromosomal loci for the TST. The QTL on chromosome 11 and its associated epistatic TST-QTL on chromosome X encode gamma-aminobutyric acid type A (GABA(A)) receptor subunits as candidates. Sequence and expression analyses of these genes from the two parental strains revealed a significantly lower expression of the alpha1 subunit gene in the frontal cortex of B6 mice compared to C3 mice. The present quantitative trait study should open up avenues for identifying novel molecular targets for antidepressants and unraveling the complex genetic mechanisms of depressive and anxiety disorders.