title: Adaptive changes in serotonin metabolism preserve normal behavior in mice with reduced TPH2 activity.
abstract: Polymorphisms in the TPH2 gene coding for the serotonin synthesizing enzyme in the brain are considered as risk factors associated with depression and anxiety in humans. However, whether a certain variation in the TPH2 gene leads to decreased brain serotonin production and development of psychological abnormalities remains unresolved. We generated a new mouse model, carrying one Tph2-null allele and one Tph21473G-allele, coding for a hypoactive form of the enzyme. We tested these mice along with C57BL/6 mice (Tph2C/C), congenic C57BL/6 mice homozygous for the Tph21473G-allele (Tph2G/G), and heterozygous Tph2-deficient mice (Tph2C/-) for anxiety- and depression-like behavior, and evaluated brain serotonin metabolism and 5-HT1AR signaling by high-performance liquid chromatography and quantitative autoradiography, respectively. Progressive reduction in TPH2 activity had no effect on emotional behavior, and only slightly affected brain serotonin levels. However, serotonin degradation rate was drastically decreased in mice with reduced TPH2 activity, thereby compensating for the lowered rate of serotonin production in these mice. In addition, the hypothermic response to the 5-HT1AR agonist, 8-OH-DPAT, was attenuated in mice with reduced serotonin production. In contrast, 5-HT1A autoreceptor density and G-protein coupling were not changed in mice with gradual decrease in central serotonin. Taken together, these data suggest that in conditions of reduced serotonin production lowered serotonin degradation rate contributes to the maintenance of brain serotonin at levels sufficient for adequate behavior responses. These findings reveal that decreased TPH2 activity cannot be considered a reliable predisposition factor for impaired emotional behavior.
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mosienko
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany; Humboldt-Universität Berlin, Berlin, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Matthes
authors.affiliation: Institute of Psychopharmacology at the Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hirth
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany; Humboldt-Universität Berlin, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beis
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Flinders
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Institute of Psychopharmacology at the Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany. Electronic address: alenina@mdc-berlin.de.
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D003863:Depression / Q000503:physiopathology; D005260:Female; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D009483:Neuropsychological Tests; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: 5-HT(1A) receptor; Anxiety; Depression-like behavior; Gene polymorphism; Serotonin; TPH2