Growth retardation and altered autonomic control in mice lacking brain serotonin

Abstract

Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice (Tph2 ؊/؊ ) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in Tph2 ؊/؊ mice. Moreover, Tph2 ؊/؊ females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life.growth retardation ͉ maternal care ͉ respiration ͉ serotonin ͉ sleep S erotonin (5-hydroxytryptamine, 5-HT) is an extracellular signaling molecule with a multitude of functions in the central nervous system (CNS) and in the periphery. 5-HT effects are conveyed by at least 13 receptors classified in 7 families, 5-HT1 to 5-HT7. Serotonin synthesis from tryptophan is initiated by the enzyme tryptophan hydroxylase (TPH) generating 5-hydroxytryptophan followed by aromatic amino acid decarboxylase (AADC), which produces 5-HT. We have recently discovered that 2 TPH isoenzymes exist in all vertebrates, TPH1 and TPH2, encoded by 2 distinct genes (1, 2). Tph1 is mainly expressed in the gut, generating serotonin that is distributed into the whole body by thrombocytes, and in the pineal gland, where the resulting 5-HT is metabolized to melatonin. The Tph1-deficient mice generated by us (2) and others (3, 4) revealed that 95% of peripheral 5-HT is produced by TPH1. They also revealed that 5-HT in platelets and other peripheral cells is involved in such diverse processes as thrombosis (5), liver regeneration (6), hepatitis (7), colon cancer (8), mammary gland plasticity (9), pulmonary hypertension (10), and bone formation (11). TPH2, on the other hand, is responsible for the synthesis of serotonin in the raphé nuclei of the brainstem, from where all central serotonergic projections originate (12). Accordingly, polymorphisms and functional mutations in the human and mouse genes for this enzyme have been linked to neurological and behavioral abnormalities (13)(14)(15)(16).In this study, we generated mice lacking TPH2 by gene targeting and analyzed the physiological consequences resulting from a lack of brain serotonin. Results and DiscussionGeneration and Basic Characteristics of Tph2-Deficient Mice. Tph2-deficient (Tph2 Ϫ/Ϫ ) mice were generated by deleting the coding sequence in exons 1 and 2 (supporting information (SI) Fig. S1 A and B). In the resulting Tph2 Ϫ/Ϫ mice, no Tph2 mRNA could be found by RT-PCR (Fig. S1C) and in situ hybridization in the brain (Fig. 1A). Immu...

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…Following Tph2 inactivation, growth retardation but normalization after weaning (with normal weight four months of age) was also observed by Alenina et al [21]. In contrast, it was reported that Tph2 2/2 mice display a reduced fat pad and size and that, at one and a half and three months, they display both reduced food intake and increased metabolism linked to altered leptin regulation [131].…”

“…Elimination of 5-HT synthesis does not appear to affect GABA concentrations in whole-brain tissue [21], but measurement in different brain regions of Tph2 KO mice in combination with unbiased stereological assessment of GABAergic cell subpopulations in the hippocampus and amygdala revealed differential alterations [102]. While hippocampal GABA concentrations were increased in Tph2 2/2 mice, GABA was increased in heterozygous Tph2 þ/2 mice in the amygdala compared with Tph2 2/2 and wild-type control mice but opposite in prefrontal cortex.…”

Serotonin controlling feeding and satiety

“…There are two isoforms of the enzyme; Tph1 which is predominantly expressed in the periphery, whereas Tph2 is predominantly expressed in the brain [38]. A Tph2 knockout in mice leads to retarded growth and lower body weight in early postnatal development [39,40]. An independent study found decreased food intake and bone mass in these mice [41] and the effects on body weight could possibly be gender dependent [42].…”

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

“…The generation of Tph2 -/-and SERT -/-mice has been described in detail elsewhere [15,20]. Both Tph2 -/-and SERT -/-mice have been established on a pure C57BL/6 genetic background [21].…”