The Tail Suspension Test (TST) which measures behavioral despair is widely

The Tail Suspension Test (TST) which measures behavioral despair is widely used as an animal model of human depressive disorders and antidepressant efficacy. affecting general activity but it had no effect on behavior in NZB mice. This work suggests that GABRA3 regulates a behavioral endophenotype of depression and establishes this gene BMN673 as a viable new target for the study and treatment of human depression. Electronic supplementary material The online version of this article (doi:10.1007/s00335-010-9266-6) contains supplementary material which is available to authorized users. Introduction Major depressive disorder (MDD) has a lifetime prevalence rate of approximately 20% and accounts for up to 80% of affective illnesses (Kessler et al. 2003). There is a significant genetic component to MDD as twin and adoption studies indicate that the disorder has a 40-60% heritability rate (Sullivan et al. 2000). However the complex heterogeneous nature of depression has stymied identification of causative genes. To date gene identification has been based primarily on a candidate gene approach informed by the hypothesized mode of action of antidepressant drugs on the monoaminergic system (Peters et al. 2004). However the candidate gene approach is hindered by our limited understanding of the biology of depression: There are likely to be a number of unknown genes that regulate the propensity for depression in addition to those directly BMN673 targeted by current pharmacological agents. Genome-wide association studies (GWAS) offer an unbiased means to identify causative genes but such studies generally have been unsuccessful when applied to psychiatric disorders (Craddock et al. 2005). A number of the confounding variables associated with human studies including the effects of genetic background and the environment can be minimized by BMN673 using animal models. Several behavioral tests that approximate discrete endophenotypes of human depression have been established including the Tail Suspension Test (TST) and the Forced Swim Test (FST) (Cryan and Mombereau 2004; Porsolt et al. 1977). In both tests the immobility observed when an animal is faced with an inescapable stress is believed to represent behavioral despair. While no animal model can fully recapitulate the range of symptoms associated with depressive disorders the relevance of the TST and FST to human depression has been extensively documented. First deletion or overexpression of genes linked to human depression affects immobility in the TST and FST (Cryan et al. 2005; Urani et al. 2005). Second antidepressant treatment reduces immobility in the TST and FST while antipsychotic treatment has no effect (Crowley et al. 2004). Finally factors that increase the susceptibility to depression in humans such as amphetamine withdrawal and chronic social stress increase immobility in the TST (Cryan and Mombereau 2004). Inbred mouse strains differ in their propensity Mouse monoclonal to HDAC3 for behavioral despair (Jacobson and Cryan 2007). As this effect is BMN673 highly heritable the F2 offspring of an intercross between two strains can be used to map the genetic determinants of baseline TST behavior. Several groups have used quantitative trait locus (QTL) mapping to BMN673 identify loci believed to regulate variability in TST performance (Lad et al. 2007; Liu et al. 2007; Tomida et al. 2009; Turri et al. 2001; Yoshikawa et al. 2002). However these experiments have not generated overlapping loci and the results have not been independently replicated. Furthermore the QTLs generally range from 20 to 40?Mb in size making candidate gene identification difficult. Indeed with the exception of a single study this method has not resulted in the identification of specific quantitative trait genes (Tomida et al. 2009). We recently completed a survey of baseline behavior in 33 inbred mouse strains and found that TST baseline immobility ranges from 7 to 60% in a strain-dependent manner. In the present study two mapping populations were created by crossing strains at opposite ends of this distribution: The low-immobility strain RIIIS/J (R3) was crossed with either the high-immobility C57BL/6J (B6) or NZB/BlNJ (NZB) strain. F2 offspring were phenotyped in the TST and genotyped at approximately 5-Mb intervals. Interval mapping conducted for BMN673 each cross separately identified a significant B6-specific QTL on MMU6 and a.