Abstract
Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.
Highlights
Serotonin is an important neurotransmitter that broadly functions in the regulation of multiple physiological systems, including the cardiovascular, pulmonary, gastrointestinal, genitourinary systems and the central nervous system (CNS)[1]
The wide-ranging importance of serotonin to physiological, neuropsychological and behavioral processes underscores the critical need to understand the molecular mechanisms of serotonin deficiency
Serotonin deficiency is seen in a wide range of disease, including depression[19,20], Alzheimer’s disease[21,22], Parkinson’s disease[23,24] and schizophrenia[12,25], among others
Summary
Serotonin is an important neurotransmitter that broadly functions in the regulation of multiple physiological systems, including the cardiovascular, pulmonary, gastrointestinal, genitourinary systems and the central nervous system (CNS)[1]. Efforts to understand serotonin functionality and signaling mechanisms have primarily focused on its 12 heterotrimeric guanine nucleotide binding protein-coupled receptors and one additional ligand-gated ion channel which have been grouped into seven distinct classes (5-HT1 to 5-HT7)[4]. One such example is behavioral aggression which is regulated by 5-HT1A, 5-HT1B and 5-HT2A receptors[8,9,10]; the 5-HT1B receptor modulates aggression and migraine, locomotion, drug abuse reinforcement, depression and anxiety[11] These complicated, non-specific receptor-phenotype relationships represent a significant shortcoming in receptor-based approaches to understand serotonin pathophysiology. Ultra-performance liquid chromatography - mass spectrometry was used to pilot novel biomarkers and metabolic pathways in both non-targeted and targeted metabolomics manners and elucidate the fine serotonin deficiency-associated molecular mechanisms
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