Tph2, short for tryptophan hydroxylase 2, is the rate-limiting enzyme in brain serotonin synthesis. Serotonin is involved in numerous physiological, behavioral, and cognitive processes, and thus Tph2 is of great biological importance. Genetic models, especially gene knockout mouse models, have been crucial in understanding Tph2's functions [1,2,3,4,5,6,7].

In Tph2-deficient mice (Tph2 -/-), ethanol consumption increased, suggesting central 5-HT, synthesized by Tph2, is an important modulator of drinking behavior [2]. Adult-onset Tph2 deletion in the dorsal Raphe nuclei (DRN) of male mice led to hyperphagia and weight gain, indicating Tph2 in the DRN contributes to energy balance regulation in a sex-dependent manner [3]. Deletion of TLR4 in Tph2 neurons decreased anxiety-like behaviors in male mice, showing TLR4 in Tph2 neurons modulates anxiety-related behaviors in a sex-dependent way [4]. Mice with a Tph2 mutation (TPH2-R439H) had reduced 5-HT in enteric neurons, leading to defects in enteric nervous system (ENS) development and gastrointestinal (GI) motility [6]. Tph2 conditional knockout (Tph2 CKO) in APP/PS1 mice increased amyloid-β (Aβ) plaque load and astrogliosis, suggesting Tph2 plays a role in amyloid plaque generation [7].

In conclusion, Tph2 is essential for regulating serotonin synthesis in the brain, which in turn impacts various biological processes. Tph2 KO/CKO mouse models have revealed its role in alcohol drinking behavior, energy balance, anxiety-related behaviors, ENS development, GI motility, and amyloid plaque formation, contributing to our understanding of related diseases such as alcohol-related disorders, metabolic disorders, anxiety disorders, mood-related GI disorders, and Alzheimer's disease.

References:

1. Ottenhof, Koen Willem, Sild, Mari, Lévesque, Mélissa Luce, Ruhé, Henricus Gerardus, Booij, Linda. 2018. TPH2 polymorphisms across the spectrum of psychiatric morbidity: A systematic review and meta-analysis. In Neuroscience and biobehavioral reviews, 92, 29-42. doi:10.1016/j.neubiorev.2018.05.018. https://pubmed.ncbi.nlm.nih.gov/29775696/

2. Zaniewska, Magdalena, Mosienko, Valentina, Bader, Michael, Alenina, Natalia. 2022. Tph2 Gene Expression Defines Ethanol Drinking Behavior in Mice. In Cells, 11, . doi:10.3390/cells11050874. https://pubmed.ncbi.nlm.nih.gov/35269497/

3. Liu, Hailan, Wang, Chunmei, Yu, Meng, Hu, Fang, Xu, Yong. . TPH2 in the Dorsal Raphe Nuclei Regulates Energy Balance in a Sex-Dependent Manner. In Endocrinology, 162, . doi:10.1210/endocr/bqaa183. https://pubmed.ncbi.nlm.nih.gov/33034617/

4. Li, Yongxiang, Zhu, Shuqing, Xie, Kailai, Jiang, Qingyan, Wang, Lina. 2022. TLR4 in Tph2 neurons modulates anxiety-related behaviors in a sex-dependent manner. In Neuropharmacology, 216, 109175. doi:10.1016/j.neuropharm.2022.109175. https://pubmed.ncbi.nlm.nih.gov/35787402/

5. Pratelli, Marta, Pasqualetti, Massimo. 2018. Serotonergic neurotransmission manipulation for the understanding of brain development and function: Learning from Tph2 genetic models. In Biochimie, 161, 3-14. doi:10.1016/j.biochi.2018.11.016. https://pubmed.ncbi.nlm.nih.gov/30513372/

6. Israelyan, Narek, Del Colle, Andrew, Li, Zhishan, Caron, Marc G, Margolis, Kara G. 2019. Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression. In Gastroenterology, 157, 507-521.e4. doi:10.1053/j.gastro.2019.04.022. https://pubmed.ncbi.nlm.nih.gov/31071306/

7. Xu, Chao-Jin, Wang, Jun-Ling. . Tph2 Genetic Ablation Contributes to Senile Plaque Load and Astrogliosis in APP/PS1 Mice. In Current Alzheimer research, 16, 219-232. doi:10.2174/1567205016666190301110110. https://pubmed.ncbi.nlm.nih.gov/30827242/