Targeted Manipulation of Brain Serotonin: RNAi-Mediated Knockdown of Tryptophan Hydroxylase 2 in Rats

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT). Two existing TPH isoforms are responsible for the generation of two distinct serotonergic systems in vertebrates. TPH1, predominantly expressed in gastrointestinal tract and pineal gland, mediates 5-HT biosynthesis in non-neuronal tissues, while TPH2, mainly found in the raphe nuclei of the hindbrain, is accountable for the production of 5-HT in the brain. Neuronal 5-HT is a key regulator of mood and behaviour and its deficiency has been implicated in a variety of neuropsychiatric disorders, e.g. depression and anxiety. To gain further insights into the complexity of central 5-HT modulations of physiological and pathophysiological processes, a new transgenic rat model, allowing an inducible gene knockdown of Tph2 was established based on doxycycline-inducible shRNA-expression. Biochemical phenotyping revealed a functional knockdown of Tph2 mRNA expression following ...