Tryptophan hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models

ABSTRACT

Introduction: Tryptophan hydroxylase 2 (TPH2) is the key, rate-limiting enzyme of serotonin (5-HT) synthesis in the brain. Some polymorphic variants of the human Tph2 gene are associated with psychiatric disorders.

Area covered: This review focuses on the mechanisms underlying the association between the TPH2 activity and behavioral disturbances in models of psychiatric disorders. Specifically, it discusses: 1) genetic and posttranslational mechanisms defining the TPH2 activity, 2) behavioral effects of knockout and loss-of-function mutations in the mouse Tph2 gene, 3) pharmacological inhibition and the activation of the TPH2 activity and 4) alterations in the brain TPH2 activity in animal models of psychiatric disorders. We show the dual role of the TPH2 activity: both deficit and excess of the TPH2 activity cause significant behavioral disturbances in animal models of depression, anxiety, aggression, obsessive-compulsive disorders, schizophrenia, and catalepsy.

Expert opinion: Pharmacological chaperones correcting the structure of the TPH2 molecule are promising tools for treatment of some hereditary psychiatric disorders caused by loss-of-function mutations in the human Tph2 gene; while some stress-induced affective disorders, associated with the elevated TPH2 activity, may be effectively treated by TPH2 inhibitors. This dual role of TPH2 should be taken into consideration during therapy of psychiatric disorders.

KEYWORDS:

• Tryptophan hydroxylase 2
• loss-of-function mutations
• models of psychiatric disorders
• inhibitors
• pharmacological chaperones

Article highlights

• Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme of serotonin synthesis in the brain, and it is a potential therapeutic target for psychiatric disorders.

• Clinical and experimental studies show a dual role of TPH2 in psychiatric disorders: both deficit and excess of TPH2 activity are associated with psychiatric disorders and behavioral disturbances in animal models of psychiatric disorders.

• Some polymorphisms in the human Tph2 gene are associated with affective disorders. The R439H loss-of-function mutation in the mouse Tph2 gene increases the depressive-like and obsessive-compulsive-like traits in Tph2KI mice.

• The level of Tph2 gene mRNA is increased in the raphe nuclei of depressive patients. Stress increases TPH2 activity and expression in the rat brain.

• Pharmacological chaperones correcting the structure of mutant TPH2 molecule are promising tools for treatment of some psychiatric disorders caused by loss-of-function mutations in the human Tph2 gene.

• TPH2 inhibitors can be effective for correction of the enzyme hyperactivity associated withstress-induced affective disorders and catalepsy.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of the authors is supported by the Russian Science Foundation (grant No 17-15-01032)