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

BMC Genetics

Research Article

Isaäc J Nijman¹  Sylvia Kuijpers¹  Edwin Cuppen¹  Judith Homberg² 

[1] Hubrecht Institute & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands;Hubrecht Institute & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands;Donders Institute for Brain, Cognition, and Behavior, Centre for Neuroscience, Dept. of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 EZ, Nijmegen, The Netherlands;

关键词: Cocaine;    Genetic Modifier;    White Adipose Tissue;    Brown Norway;    Exploratory Pattern;   

DOI  :  10.1186/1471-2156-11-37

 received in 2009-10-27, accepted in 2010-05-07,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundGenetic 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.ResultsIn 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).ConclusionsWe 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.

【 授权许可】

Unknown   
© Homberg et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.