Modulation of Serotonin Synthesis, Reuptake, and Degradation by 1,25‐Dihydroxyvitamin D: Potential Relevance for Neuropsychiatric Disorders
Authors: Sabir Marya S. , Dussik Christopher M. , Kaneko Ichiro , Whitfield G. Kerr , Haussler Mark R. , Jurutka Peter W. 
Published: November 2023

The two compounds, 1,25‐dihydroxyvitamin D (1,25D, vitamin D) and 5‐hydroxytryptamine (5‐HT, serotonin), have been proposed to play a significant role in abnormal social behavior associated with psychological conditions including autism spectrum disorders (ASDs) and depression; however, the mechanism underlying these associations has yet to be elucidated. Deficiencies in 1,25D or 5‐HT have been linked to the increased incidence of ASDs. Thus, examining the modulation of genes involved in 5‐HT biosynthesis, reuptake, and degradation is fundamental in linking low 1,25D levels to the increased incidence of psychiatric disorders. We propose that 1,25D regulates tryptophan hydroxylase‐1/2 (TPH1/2), the initial and rate‐limiting enzyme in the biosynthetic pathway of 5‐HT, the serotonin transporter (SERT), and the enzyme(s) responsible for serotonin catabolism i.e., monoamine oxidase (MAO). In this study, quantitative real time‐PCR (qPCR) was utilized to examine TPH1/2 expression in cultured human glioblastoma (U‐87) cells and rat serotonergic neurons (B‐14). TPH1 induction in U‐87 and B‐14 cells was approximately 1.8‐fold and 24.6‐fold, respectively, at 10 nM 1,25D. Human TPH2 mRNA in U‐87 cells was induced dose‐dependently resulting in a 2.4‐fold increase at 10 nM 1,25D. Strikingly, TPH2 mRNA in B‐14 cells was observed to be 26‐ to 86‐fold upregulated at 10 nM 1,25D; however, 1 nM and 100 nM 1,25D elicited significantly smaller inductions (8‐fold and 1.2‐fold, respectively). The biphasic dose response of TPH2 expression in B‐14 cells may signify the existence of an optimal level of circulating 1,25D for behavioral health corresponding empirically to 10 nM 1,25D in the case of B‐14 treatment, suggesting that this effective level of 1,25D may elicit normal neurotransmission and development. Next, we examined mRNA expression of the serotonin transporter which regulates the serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations, and also exists as a target for the SSRI‐class of antidepressants. Our novel results revealed that SERT expression was significantly repressed in 10 nM 1,25D‐treated B‐14 cells, in contrast to the results obtained in U‐87. Furthermore, examination of MAOA via qPCR displayed significant repression in 1 nM and 10 nM 1,25D‐treated B‐14 cells, while U‐87 MAOA expression demonstrated an upregulation at identical 1,25D concentrations. Given the profile of gene regulation in B‐14 serotonergic neurons, the production of 5‐HT was predicted to increase in response to 1,25D, a hypothesis that was tested via serotonin ELISA analysis. In summary, the upregulation of TPH1/2, coupled with the repression of SERT and MAOA genes by 1,25D in B‐14 cells increases both intracellular and extracellular serotonin concentrations, thus potentially reversing the effects of pathophysiologies resulting from dysregulation of serotonergic neurotransmission.Support or Funding InformationNational Institutes of Health Grants DK033351 to MRH and CA140285 to PWJ.