ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2012
A functional Tph2 C1473G polymorphism causes an anxiety phenotype via compensatory changes in the serotonergic system.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 28 citations in OpenAlex.
- Bile duct ligation elevates 5-HT levels in cerebral cortex of rats partly due to impairment of brain UGT1A6 expression and activity via ammonia accumulation.Redox biology · 2024Article
- Pianp deficiency links GABAMolecular psychiatry · 2020Article
- Novel aspects of enteric serotonergic signaling in health and brain-gut disease.American journal of physiology. Gastrointestinal and liver physiology · 2020Review
- Comprehensive behavioral analysis and quantification of brain free amino acids of C57BL/6J congenic mice carrying the 1473G allele in tryptophan hydroxylase-2.Neuropsychopharmacology reports · 2019Article
- Loss of Adult 5-HT1A Autoreceptors Results in a Paradoxical Anxiogenic Response to Antidepressant Treatment.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice.Translational psychiatry · 2017Article
- Genetic influences on social attention in free-ranging rhesus macaques.Animal behaviour · 2015Article
- Adult AMPA GLUA1 receptor subunit loss in 5-HT neurons results in a specific anxiety-phenotype with evidence for dysregulation of 5-HT neuronal activity.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2015Article
- Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system.The international journal of neuropsychopharmacology · 2014Article
- Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype.ACS chemical neuroscience · 2014Article
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10 authors at 5 institutions in 3 countries.
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Abstract
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-γ-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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