Molecular neuroscienceCharacterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system
Section snippets
Animals
All experiments were approved by the Animal Care Committee of the Royal Dutch Academy of Science, the Free University of Amsterdam, the Radboud University Nijmegen, and the University of Groningen according to the Dutch legal ethical guidelines. Experiments were designed to minimize the number of required animals and their suffering.
The SERT knockout rat (Slc6a41Hubr) was generated by target-selected ENU-induced mutagenesis (for detailed description, see Smits et al., 2006). Briefly,
SERT knockout rat characteristics
High-throughput resequencing of target genes in a library of ENU-mutagenized rats (Smits et al., 2006) revealed a C to A transversion at position 3924 (relative to the start codon in ENSRNOG0000003476) in the SERT gene, resulting in a premature stop codon (TGC>TGA) in the third exon encoding the second extracellular loop (Fig. 1A), and thereby most likely resulting in a non-functional protein product. Northern blot analysis (Fig. 1B and C) revealed that the premature stop codon results in
Discussion
Using the recently established gene knockout technology (Zan et al 2003, Smits et al 2004, Smits et al 2006) we obtained a rat knockout for the SERT gene, and here we present the first comprehensive characterization of this novel model. We show that the ENU-induced premature stop codon results into a complete lack of SERT, and interestingly, that SERT+/− rats show a gene-dosage effect with respect to SERT expression and function. The SERT+/− rat may therefore be a novel model system for
Acknowledgments
We thank J. Vermond for his help with enzymatic measurements, F. Hogenboom and G. Wardeh for technical support with the superfusion experiments, and N. Leguit for HPLC analysis. This work was supported by the Dutch Ministry of Economic Affairs through the Innovation Oriented Research Program on Genomics (IGE1017) and the award “Exploiting natural and induced genetic variation in the laboratory rat” to EC from the European Heads of Research Councils and European Science Foundation EURYI
References (50)
- et al.
Vulnerability to mild predator stress in serotonin transporter knockout mice
Behav Brain Res
(2006) - et al.
Nonsense-mediated mRNA decay: terminating erroneous gene expression
Curr Opin Cell Biol
(2004) - et al.
Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis
Brain Res Brain Res Rev
(1998) - et al.
Somato-dendritic 5-HT1A autoreceptors in the dorsal raphe nucleus: pharmacological and functional properties
- et al.
Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter
Neuropsychopharmacology
(2002) - et al.
Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter
Neuropharmacology
(2005) - et al.
Altered depression-related behaviours and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice
Biol Psychiatry
(2003) - et al.
Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression
J Neurosci Methods
(2004) - et al.
Plasticity in serotonin uptake in primary neuronal cultures of serotonin transporter knockout mice
Brain Res Dev Brain Res
(2001) - et al.
Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland
Biol Psychiatry
(2004)
Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study
Life Sci
Mu,- delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate
Eur J Pharmacol
Target-selected mutagenesis of the rat
Genomics
Radioenzymatic assay for tryptophan hydroxylase: [3H]H2O release assessed by charcoal adsorption
J Neurosci Methods
Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative
Brain Res
Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder
Mol Psychiatry
Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (‘ecstasy’) in serotonin transporter-deficient mice
Mol Pharmacol
Effects of chronic antidepressant treatments on serotonin transporter function, density and mRNA level
J Neurosci
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade
Neuropsychopharmacology
In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters
J Pharmacol Exp Ther
Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter
Eur J Neurosci
Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates
Am J Med Genet B Neuropsychiatr Genet
Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study
J Pharmacol Exp Ther
Genetic variation in the serotonin transporter promotor region affects serotonin uptake in human blood platelets
Am J Med Genet
Cited by (0)
- 1
Present address: Evotec Pharmaceutical Division, Neuropharmacology, Hamburg, Germany (B. A. Ellenbroek); McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, USA (B. M. G. Smits).