Functional Coding Variation in Recombinant Inbred Mouse Lines Reveals Novel Serotonin Transporter-Associated Phenotypes

Journal Article · Thu Jan 01 04:00:00 EST 2009 · Proceedings of the National Academy of Sciences

DOI:https://doi.org/10.1073/pnas.0809449106· OSTI ID:948539

Carneiro, Ana ^[1]; Airey, David ^[2]; Thompson, Brent ^[1]; Zhu, C ^[1]; Rinchik, Eugene M ^[3]; Lu, Lu ^[2]; Chesler, Elissa J ^[3]; Erikson, Keith ^[4]; Blakely, Randy ^[1]

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1. Vanderbilt University
2. University of Tennessee Health Science Center, Memphis
3. ORNL
4. University of North Carolina

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology or treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism and obsessive-compulsive disorder (OCD). Here we utilize naturally occurring polymorphisms in recombinant inbred (RI) lines to identify novel phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by two nonsynonymous coding variants (Gly39 and Lys152 (GK)). At these positions, many other mouse lines, including DBA/2J, encode Glu39 and Arg152 (ER haplotype), assignments found also in hSERT. Synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant. Heterologous expression studies confirmed a reduced SERT turnover rate for the GK variant. Experimental and in silico approaches using RI lines (C57Bl/6J X DBA/2J=BXD) identifies multiple anatomical, biochemical and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are multiple traits associated with anxiety and alcohol consumption, as well as of the control of dopamine (DA) signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates ironregulated DA phenotypes. Our studies provide a novel example of the power of coordinated in vitro, in vivo and in silico approaches using murine RI lines to elucidate and quantify the system-level impact of gene variation.

• Research Organization: Oak Ridge National Laboratory (ORNL); Mouse Genetics Research Facility
• Sponsoring Organization: SC USDOE - Office of Science (SC)
• DOE Contract Number: AC05-00OR22725
• OSTI ID: 948539
• Journal Information: Proceedings of the National Academy of Sciences, Journal Name: Proceedings of the National Academy of Sciences Journal Issue: 6 Vol. 106; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ALCOHOLS
DOPAMINE
ETIOLOGY
EVALUATION
FUNCTIONALS
GENES
HOMEOSTASIS
IN VITRO
IN VIVO
IRON
MICE
SEROTONIN
STRAINS
TRANSPORT