@article{GutknechtAraragiMerkeretal.2012,
  author    = {Gutknecht, Lise and Araragi, Naozumi and Merker, S{\"o}ren and Waider, Jonas and Sommerlandt, Frank M. J. and Mlinar, Boris and Baccini, Gilda and Mayer, Ute and Proft, Florian and Hamon, Michel and Schmitt, Angelika G. and Corradetti, Renato and Lanfumey, Laurence and Lesch, Klaus-Peter},
  title     = {Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0043157},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133728},
  year      = {2012},
  abstract  = {Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2). Tph2 inactivation (Tph2-/-) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT\(_{1A}\) and 5-HT\(_{1B}\) receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.},
  language  = {en}
}
@article{KarabegGrauthoffKollertetal.2013,
  author    = {Karabeg, Margherita M. and Grauthoff, Sandra and Kollert, Sina Y. and Weidner, Magdalena and Heiming, Rebecca S. and Jansen, Friederike and Popp, Sandy and Kaiser, Sylvia and Lesch, Klaus-Peter and Sachser, Norbert and Schmitt, Angelika G. and Lewejohann, Lars},
  title     = {5-HTT Deficiency Affects Neuroplasticity and Increases Stress Sensitivity Resulting in Altered Spatial Learning Performance in the Morris Water Maze but Not in the Barnes Maze},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0078238},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129978},
  pages     = {e78238},
  year      = {2013},
  abstract  = {The purpose of this study was to evaluate whether spatial hippocampus-dependent learning is affected by the serotonergic system and stress. Therefore, 5-HTT knockout (-/-), heterozygous (+/-) and wildtype (+/+) mice were subjected to the Barnes maze (BM) and the Morris water maze (WM), the latter being discussed as more aversive. Additionally, immediate early gene (IEG) expression, hippocampal adult neurogenesis (aN), and blood plasma corticosterone were analyzed. While the performance of 5-HTT-/- mice in the BM was undistinguishable from both other genotypes, they performed worse in the WM. However, in the course of the repeated WM trials 5-HTT-/- mice advanced to wildtype level. The experience of a single trial of either the WM or the BM resulted in increased plasma corticosterone levels in all genotypes. After several trials 5-HTT-/- mice exhibited higher corticosterone concentrations compared with both other genotypes in both tests. Corticosterone levels were highest in 5-HTT-/- mice tested in the WM indicating greater aversiveness of the WM and a greater stress sensitivity of 5-HTT deficient mice. Quantitative immunohistochemistry in the hippocampus revealed increased cell counts positive for the IEG products cFos and Arc as well as for proliferation marker Ki67 and immature neuron marker NeuroD in 5-HTT-/- mice compared to 5-HTT+/+ mice, irrespective of the test. Most differences were found in the suprapyramidal blade of the dentate gyrus of the septal hippocampus. Ki67-immunohistochemistry revealed a genotype x environment interaction with 5-HTT genotype differences in na{\"i}ve controls and WM experience exclusively yielding more Ki67-positive cells in 5-HTT+/+ mice. Moreover, in 5-HTT-/- mice we demonstrate that learning performance correlates with the extent of aN. Overall, higher baseline IEG expression and increased an in the hippocampus of 5-HTT-/- mice together with increased stress sensitivity may constitute the neurobiological correlate of raised alertness, possibly impeding optimal learning performance in the more stressful WM.},
  language  = {en}
}