title: Brain-specific conditional and time-specific inducible Tph2 knockout mice possess normal serotonergic gene expression in the absence of serotonin during adult life.
abstract: Several lines of evidence implicate a dysregulation of tryptophan hydroxylase (TPH)-dependent serotonin (5-HT) synthesis in emotional behaviour and stress, and point to its relevance for the etiology and pathogenesis of various neuropsychiatric disorders. We therefore studied different animal models featuring reduced Tph2 expression to investigate the consequences of impaired brain 5-HT synthesis on neuronal development. Specifically, brain-specific conditional and time-specific inducible Tph2 knockout (KO) models were generated and investigated for altered serotonergic neuron-specific gene expression. Raphe neurons of a brain-specific constitutive Tph2 KO were completely devoid of Tph2-positive neurons and, consequently, 5-HT in the brain, and also displayed no compensatory up-regulation of Tph1 expression. In contrast, an inducible Tph2 KO mouse facilitates the generation of a brain-specific 5-HT-reduction model selectively during adult life. This resulted in a highly reduced number of Tph2-positive cells and thus 5-HT in the brain. Intriguingly, expression studies detected no alteration in the expression of genes relevant to the 5-HT system in the brain-specific Tph2 KO and the 5-HT-reduction models. These findings confirm the specificity of Tph2 in brain 5-HT synthesis across the lifespan, yet also suggest that neither developmental nor adult 5-HT synthesis is required for the expression of genes specific for serotonergic signalling. The formation of the serotonergic system thus seems to be a preserved expressional pattern due to intrinsic cellular programs which occurs also in the absence of its key molecule, namely 5-HT.
authors.affiliation: Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Julius-Maximilians University of Würzburg, Würzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kriegebaum
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Song
authors.forename: Lise
authors.initials: L
authors.lastname: Gutknecht
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmitt
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Ding
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000235:genetics* / Q000502:physiology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D001616:beta-Galactosidase