Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification

PLoS One. 2012;7(8):e43157. doi: 10.1371/journal.pone.0043157. Epub 2012 Aug 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Autoradiography
  • Body Weight
  • Brain / metabolism*
  • Gene Silencing / physiology*
  • Growth and Development / genetics
  • Growth and Development / physiology*
  • Histological Techniques
  • Hydroxyindoleacetic Acid / metabolism
  • Mice
  • Norepinephrine / metabolism
  • Raphe Nuclei / metabolism*
  • Receptors, Serotonin / metabolism
  • Serotonin / deficiency*
  • Sex Factors
  • Tryptophan Hydroxylase / genetics*

Substances

  • Receptors, Serotonin
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase
  • Norepinephrine

Grant support

This study was supported by the German research foundation (DFG) (SFB 581, SFB TRR 58, KFO 125), IZKF (N-162) and the European Community (NEWMOOD LSHM-CT-2003-503474). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.