Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes

Kalueff, Allan V.; Olivier, Jocelien; Nonkes, Lourens J.P.; Homberg, Judith R.

doi:10.1016/j.neubiorev.2009.08.003

Cited by 184 publications

(156 citation statements)

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“…The mixed genetic background (F1 generation from matings of 129S6/SvEv mice with C57BL/6 mice) used in the study could contribute to the depressive phenotype as well. This was shown for serotonin transporter (5-HTT, Slc6A4) knockout mice, in which depressive behavior was only found when the genetic background was not 100% C57BL/6 (Kalueff et al, 2010). Together with our findings, this might suggest that additional genetic modifications absent in the C57BL/6 genetic background are necessary for eliciting depressionrelated symptoms in rodents.…”

Section: Mouse Tph2 Polymorphisms In Defined Genetic Backgroundssupporting

confidence: 83%

“…Similarly to 1473G/G mice, Slc6a4 knockout mice on a C57BL/6 background displayed elevated anxiety without depression-like alterations (Kalueff et al, 2010) and showed a lower 5-HT synthesis rate in vivo and a desensitization of 5-HT 1A autoreceptors (Fabre et al, 2000). However, while in Slc6a4 knockout mice the observed desensitization of 5-HT 1A autoreceptors is due to a reduction of its expression (Fabre et al, 2000), the concentration of 5-HT 1A autoreceptors in the dorsal raphe in our 1473G/G mice is unaltered.…”

Section: Mouse Tph2 Polymorphisms In Defined Genetic Backgroundsmentioning

confidence: 95%

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A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg 447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [ 35 S]GTP-g-S binding assay and 5-HT 1A receptor autoradiography, a functional desensitization of 5-HT 1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT 1A autoreceptors.

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Section: Mouse Tph2 Polymorphisms In Defined Genetic Backgroundssupporting

confidence: 83%

Section: Mouse Tph2 Polymorphisms In Defined Genetic Backgroundsmentioning

confidence: 95%

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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“…As SERT-knockout rats display anxiety-and depressive-like behaviors (Kalueff et al, 2010;Olivier et al, 2008), we tested whether antidepressant treatment may restore the expression of Npas4 in these animals. Therefore, we chronically treated adult SERT À/À rats with the SNRI duloxetine, (Carter and McCormack, 2009), and measured Npas4 mRNA levels in the hippocampus and prefrontal cortex.…”

Section: Effect Of Chronic Duloxetine Treatment On Npas4 Andmentioning

confidence: 99%

“…In this context, the 5-HT transporter (5-HTT in humans; serotonin transporter (SERT) in rodents) is particularly relevant, due to the presence of a human functional polymorphism within its promoter region that modulates the susceptibility to different neuropsychiatric disorders, and that may also affect antidepressant response (Caspi et al, 2003;Huezo-Diaz et al, 2009;Serretti et al, 2007;Uher and McGuffin, 2008). As the SERT polymorphism is not present in rodents (Caspi et al, 2010), its role has been extensively investigated using animal models with a genetic deletion of the transporter, a manipulation that leads to an anxious and depressive phenotype (Homberg and Lesch, 2011;Kalueff et al, 2010;Murphy and Lesch, 2008;Olivier et al, 2008). Accordingly, we used targetdirected mutagenesis to generate SERT-knockout rats (Smits et al, 2006), which present an impaired serotonergic system and are characterized by anxiety-and depressionlike behavioral alterations (Homberg et al, 2007;Kalueff et al, 2010;Olivier et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…As the SERT polymorphism is not present in rodents (Caspi et al, 2010), its role has been extensively investigated using animal models with a genetic deletion of the transporter, a manipulation that leads to an anxious and depressive phenotype (Homberg and Lesch, 2011;Kalueff et al, 2010;Murphy and Lesch, 2008;Olivier et al, 2008). Accordingly, we used targetdirected mutagenesis to generate SERT-knockout rats (Smits et al, 2006), which present an impaired serotonergic system and are characterized by anxiety-and depressionlike behavioral alterations (Homberg et al, 2007;Kalueff et al, 2010;Olivier et al, 2008). We have previously demonstrated that SERT knockout (SERT À/À ) rats have altered neuronal plasticity, as indicated by the reduction of activity-regulated cytoskeleton associated protein (Arc) and of brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus and prefrontal cortex (Molteni et al, 2009b;Molteni et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Guidotti

Calabrese

Auletta

et al. 2011

Neuropsychopharmacol

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Alterations of the serotonergic system are involved in the pathophysiology of mood disorders and represent an important target for its pharmacological treatment. Genetic deletion of the serotonin transporter (SERT) in rodents leads to an anxious and depressive phenotype, and is associated with reduced neuronal plasticity as indicated by decreased brain-derived neurotrophic factor (Bdnf) expression levels. One of the transcription factors regulating Bdnf is the neuronal PAS domain protein 4 (Npas4), which regulates activitydependent genes and neuroprotection, and has a critical role in the development of GABA synapses. On the basis of these premises, we investigated the expression of Npas4 and GABAergic markers in the hippocampus and prefrontal cortex of homozygous (SERT À/À ) and heterozygous (SERT + /À ) knockout rats, and analyzed the effect of long-term duloxetine treatment on the expression of these targets. We found that Npas4 expression was reduced in both the brain structures of adult SERT + /À and SERT À/À animals. This effect was already present in adolescent SERT À/À , and could be mimicked by prenatal exposure to the antidepressant fluoxetine. Moreover, SERT À/À rats showed a strong impairment of the GABAergic system, as indicated by the reduction of several markers, including the vesicular transporter (Vgat), glutamic acid decarboxylase-67 (Gad67), the receptor subunit GABA A receptor, gamma 2 (GABA A -g2), and calciumbinding proteins that label subgroups of the GABAergic neurons. Interestingly, chronic treatment with the antidepressant duloxetine was able to restore the physiological levels of Npas4 and GABAergic markers in SERT À/À rats, although some differences in the modulation of GABAergic genes exist between hippocampus and prefrontal cortex. Our results demonstrate that SERT knockout rats, an animal model of mood disorders, have reduced Npas4 expression that correlates with decreased expression of Bdnf exon I and IV. These changes lead to an impairment of the GABAergic system that may contribute to the anxious and depressive phenotype associated with inherited SERT downregulation.

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Serotonin States and Social Anxiety

Stein

Andrews

2015

JAMA Psychiatry

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Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes

Cited by 184 publications

References 151 publications

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Serotonin States and Social Anxiety

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