Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.
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.
Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany. Gutknecht.Lise@yahoo.fr
Lise
L
Gutknecht
Naozumi
N
Araragi
Sören
S
Merker
Jonas
J
Waider
Frank M J
FM
Sommerlandt
Boris
B
Mlinar
Gilda
G
Baccini
Ute
U
Mayer
Florian
F
Proft
Michel
M
Hamon
Angelika G
AG
Schmitt
Renato
R
Corradetti
Laurence
L
Lanfumey
Klaus-Peter
KP
Lesch
D000367:Age Factors; D000818:Animals; D001345:Autoradiography; D001835:Body Weight; D001921:Brain / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology*; D048788:Growth and Development / Q000235:genetics / Q000502:physiology*; D006652:Histological Techniques; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency*; D012737:Sex Factors; D014365:Tryptophan Hydroxylase / Q000235:genetics*
D011985:Receptors, Serotonin; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D009638:Norepinephrine