Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants

Abstract

The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesis of serotonin is regulated by two rate-limiting enzymes, tryptophan hydroxylase-1 and -2 (TPH1 and TPH2). We used a gene-targeting approach to generate mice with selective and complete elimination of the two known TPH isoforms. This resulted in dramatically reduced central 5-HT levels in Tph2 knockout (TPH2KO) and Tph1/Tph2 double knockout (DKO) mice; and substantially reduced peripheral 5-HT levels in DKO, but not TPH2KO mice. Therefore, differential expression of the two isoforms of TPH was reflected in corresponding depletion of 5-HT content in the brain and periphery. Surprisingly, despite the prominent and evolutionarily ancient role that 5-HT plays in both vertebrate and invertebrate physiology, none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered. These behavioral changes were subtle in the TPH2KO mice; they were enhanced in the DKO mice. Herein, we confirm findings from prior descriptions of TPH1 knockout mice and present the first reported phenotypic evaluations of Tph2 and Tph1/Tph2 knockout mice. The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders.

Severe Serotonin Depletion after Conditional Deletion of the Vesicular Monoamine Transporter 2 Gene in Serotonin Neurons: Neural and Behavioral Consequences

“…All recent genetic hyposerotonergic models focused on reducing 5-HT production either by targeting the central 5-HT synthesis enzyme, TPH2 (Alenina et al, 2009;Beaulieu et al, 2008;Gutknecht et al, 2008;Savelieva et al, 2008) or by invalidating the transcription factors controlling differentiation of raphe neurons such as pet1 and lmx1B (Dai et al, 2008;Hendricks et al, 2003;Kiyasova et al, 2011;Zhao et al, 2006). The more severe 5-HT depletion observed here (À95%), compared with previous models (À70 to 90%), is likely due to the fact that increased 5-HT degradation, when VMAT2 is absent, affects all sources of 5-HT (eg, produced by TPH1/TPH2).…”

A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

“…The differences in the effect of PCPA on food intake might be due to the differences in the doses of PCPA. Tph1-deficient mice fed a high-fat diet are protected against obesity and insulin resistance via promoting thermogenesis via UCP-1 in brown adipose tissue without affecting food intake [1,2]. On the other hand, Tph2-deficient mice fed a normal diet exhibit decreased food intake and increased energy expenditure, leading to decreases in body weight and fat pad weight [1,3].…”

“…Tph1-deficient mice fed a high-fat diet are protected against obesity and insulin resistance via promoting thermogenesis via UCP-1 in brown adipose tissue without affecting food intake [1,2]. On the other hand, Tph2-deficient mice fed a normal diet exhibit decreased food intake and increased energy expenditure, leading to decreases in body weight and fat pad weight [1,3]. Although treatment with PCPA (500 mg/kg), an inhibitor of both Tph1 and Tph2, remarkably decreases brain 5-HT synthesis and serum 5-HT levels [5,6], the A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet lower dose (300 mg/kg) might be less effective on the inhibition of Tph2 in mice fed a high-fat diet.…”

“…PPARα, sense, weight, and glucose tolerance, Tph1-deficient mice fed a high-fat diet are protected against obesity, insulin resistance, and non-alcoholic fatty liver [1]. On the other hand, Tph2-deficient mice fed a normal diet exhibit decreased food intake and increased energy expenditure, leading to decreases in body weight and fat pad weight [2,3].…”

“…Tryptophan hydroxylase (Tph) is the initial and rate-limiting enzyme in the synthesis of 5-HT. Tph has two isoforms: Tph1, which is primarily expressed in peripheral tissues, and Tph2, which is expressed in neural tissues, including the central nervous system [1]. Although Tph1-deficient mice fed a normal diet display normal food intake, body…”