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

被引：88

作者：

Gutknecht, Lise ^{[1
]}

Araragi, Naozumi ^{[1
]}

Merker, Soeren ^{[1
]}

Waider, Jonas ^{[1
]}

Sommerlandt, Frank M. J. ^{[1
]}

Mlinar, Boris ^{[2
]}

Baccini, Gilda ^{[2
]}

Mayer, Ute ^{[1
]}

Proft, Florian

Hamon, Michel ^{[3
]}

Schmitt, Angelika G. ^{[1
]}

Corradetti, Renato ^{[2
]}

Lanfumey, Laurence ^{[3
]}

Lesch, Klaus-Peter ^{[1
]}

机构：

[1] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Lab Translat Neurosci, Wurzburg, Germany

[2] Univ Florence, Dept Preclin & Clin Pharmacol, Florence, Italy

[3] Natl Inst Hlth & Med Res, INSERM U894, Med Fac Pierre & Marie Curie, Ctr Psychiat & Neurosci, Paris, France

来源：

PLOS ONE | 2012年 / 7卷 / 08期

关键词：

KNOCK-OUT MICE; ENERGY-EXPENDITURE; LOCOMOTOR-ACTIVITY; 5-HT TRANSPORTER; ANXIETY-LIKE; RECEPTORS; BEHAVIOR; TRYPTOPHAN; NUCLEUS; LACKING;

D O I：

10.1371/journal.pone.0043157

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-HT1A and 5-HT1B 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.

引用

页数：12

共 46 条

[1] Growth retardation and altered autonomic control in mice lacking brain serotonin [J].