Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

Abstract

Background: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insight into serotonin transporter (SERT)-specific genetic modifiers, we studied an intercross between the Wistar SERT-/- rat and the behaviorally and genetically divergent Brown Norway rat, and performed a QTL analysis.

Results: In a cohort of >150 intercross SERT-/- and control (SERT+/+) rats we characterized 12 traits that were previously associated with SERT deficiency, including activity, exploratory pattern, cocaine-induced locomotor activity, and abdominal and subcutaneous fat. Using 325 genetic markers, 10 SERT-/--specific quantitative trait loci (QTLs) for parameters related to activity and exploratory pattern (Chr.1,9,11,14), and cocaine-induced anxiety and locomotor activity (Chr.5,8) were identified. No significant QTLs were found for fat parameters. Using in silico approaches we explored potential causal genes within modifier QTL regions and found interesting candidates, amongst others, the 5-HT1D receptor (Chr. 5), dopamine D2 receptor (Chr. 8), cannabinoid receptor 2 (Chr. 5), and genes involved in fetal development and plasticity (across chromosomes).

Conclusions: We anticipate that the SERT-/--specific QTLs may lead to the identification of new modulators of serotonergic signaling, which may be targets for pharmacogenetic and therapeutic approaches.

Figure 1

Phenotype ranges for traits recorded in the 3-day Phenotyper test, the cocaine-induced locomotor test, and for WAT traits. Solid boxes represent the 50% of trait values closest to the median (bold line). The dashed lines represent the low and high 25% of trait values. Genotypes: BN = parental BN; HOM = parental SERT^-/-; HOM2 = F2 SERT^-/-; WT = parental SERT^+/+; WT2 = F2 SERT^+/+

Figure 2

Pearson's correlation coefficients between phenotypes across F2 rats. **p < 0.004 (Bonferroni corrected). Phenotyper: DM = distance moved; IS = time in shelter; C = time in centre; Imm = time spent on immobility; mob = time spent on mobility; strm = time spent on strong mobility. Cocaine: Cc = Time in centre, C10 = distance moved during 1^st 10 min; C20 = distance moved during 2^nd 10 min; C30 = distance moved during 30-120 min White adidpose tissue (WAT): AWAT = abdominal WAT; SWAT = subcutaneous WAT