Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Ana M.D. Carneiro, David C. Airey, Brent Thompson, Chong Bin Zhu, Lu Lu, Elissa J. Chesler, Keith M. Erikson, Randy D. Blakely

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine 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 iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.

Original languageEnglish (US)
Pages (from-to)2047-2052
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number6
DOIs
StatePublished - Feb 10 2009

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Serotonin Plasma Membrane Transport Proteins
Serotonin
Phenotype
Computer Simulation
Haplotypes
Iron
Obsessive-Compulsive Disorder
Autistic Disorder
Mesencephalon
Anxiety Disorders
Computational Biology
Inbred C57BL Mouse
Knockout Mice
Alcohol Drinking
Alcoholism
Dopamine
Homeostasis
Depression
Amino Acids
Genes

All Science Journal Classification (ASJC) codes

  • General

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Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes. / Carneiro, Ana M.D.; Airey, David C.; Thompson, Brent; Zhu, Chong Bin; Lu, Lu; Chesler, Elissa J.; Erikson, Keith M.; Blakely, Randy D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 6, 10.02.2009, p. 2047-2052.

Research output: Contribution to journalArticle

Carneiro, Ana M.D. ; Airey, David C. ; Thompson, Brent ; Zhu, Chong Bin ; Lu, Lu ; Chesler, Elissa J. ; Erikson, Keith M. ; Blakely, Randy D. / Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 6. pp. 2047-2052.
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