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Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification

Please always quote using this URN: urn:nbn:de:bvb:20-opus-133728
  • 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 modelBrain 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.show moreshow less

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Metadaten
Author: Lise Gutknecht, Naozumi Araragi, Sören Merker, Jonas Waider, Frank M. J. Sommerlandt, Boris Mlinar, Gilda Baccini, Ute Mayer, Florian Proft, Michel Hamon, Angelika G. Schmitt, Renato Corradetti, Laurence Lanfumey, Klaus-Peter Lesch
URN:urn:nbn:de:bvb:20-opus-133728
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Language:English
Parent Title (English):PLoS One
Year of Completion:2012
Volume:7
Issue:8
Source:PLoS ONE 7(8): e43157. doi:10.1371/journal.pone.0043157
DOI:https://doi.org/10.1371/journal.pone.0043157
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:5-HT transporter; anxiety like; behavior; energy expenditure; knock-out mice; lacking; locomotor activity; nucleus; receptors; tryptophan
Release Date:2017/02/17
EU-Project number / Contract (GA) number:503474
OpenAIRE:OpenAIRE
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung