PLoS ONE (Jan 2012)

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

  • 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

DOI
https://doi.org/10.1371/journal.pone.0043157
Journal volume & issue
Vol. 7, no. 8
p. e43157

Abstract

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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.