Research Paper Volume 12, Issue 3 pp 3042—3052

Entorhinal cortex-based metabolic profiling of chronic restraint stress mice model of depression

Xi Chen1,3,4, *, , Tianlan Lan3,4,5, *, , Yue Wang3,4,6, *, , Yong He3,4, *, , Zhonghao Wu3,4,5, , Yu Tian2,3,4, , Yan Li2,3,4, , Mengge Bai3,4, , Wei Zhou3,4, , Hanping Zhang3,4, , Ke Cheng2,3,6, , Peng Xie1,2,3,4, ,

  • 1 Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402460, China
  • 2 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
  • 3 Chongqing Key Laboratory of Neurobiology, Chongqing 400016, China
  • 4 Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016, China
  • 5 College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
  • 6 Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
* Equal contribution

Received: November 2, 2019       Accepted: January 22, 2020       Published: February 12, 2020      

https://doi.org/10.18632/aging.102798
How to Cite

Copyright © 2020 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Despite that millions of people suffer from major depressive disorder (MDD), the mechanism underlying MDD remains elusive. Recently, it has been reported that entorhinal cortex (EC) functions on the regulation of depressive-like phenotype relying on the stimulation of glutamatergic afferent from EC to hippocampus. Based on this, we used liquid chromatography-tandem mass spectrometry method to explore metabolic alterations in the EC of mice after exposed to chronic restraint stress (CRS). Molecular validation was conducted via the application of western blot and RT-qPCR. Through this study, we found significant upregulation of glutamate, ornithine aspartic acid, 5-hydroxytryptophan, L-tyrosine and norepinephrine in CRS group, accompanied with downregulation of homovanillic acid. Focusing on these altered metabolic pathways in EC, we found that gene levels of GAD1, GLUL and SNAT1 were increased. Upregulation of SERT and EAAT2 in protein expression level were also validated, while no significant changes were found in TH, AADC, MAOA, VMAT2, GAD1, GLUL and SNAT1. Our findings firstly provide evidence about the alteration of metabolites and related molecules in the EC of mice model of depression, implying the potential mechanism in MDD pathology.

Abbreviations

MDD: major depressive disorder; EC: entorhinal cortex; LC-MS/MS: liquid chromatography-tandem mass spectrometry; CRS: chronic restraint stress; NMDA: N-methyl-d-aspartate; GABA: gamma-aminobutyric acid; UPLC: ultra-performance liquid chromatography; Trp: tryptophan; 5-HTP: 5-hydroxytryptophan; NAS: n-Acetyl-serotonin; Tra: tryptamine; Trpo: tryptophol; 5-HT: 5-hydroxytryptamine; 5-HIAA: 5-hydroxy indoleacetic acid; KYNA: kynurenic acid; 3-HA: 3-hydroxyanthranilic acid; Ind-3-C: indole-3-carboxaldehyde; Orn: ornithine; Gln: glutamine; GABA: γ-aminobutyric acid; α-KG: α-ketoglutaric acid; Glu: glutamic acid; GSH: glutathione; SA: succinic acid; Asp: aspartic acid; L-Phe: L-phenylalanine; PEA: phenylethylamine; L-Tyr: L-tyrosine; Trya: tyramine; L-DOPA: L-3,4-dihydroxyphenylalanine; DOPN: dopamine; DOPAC: 3,4-dihydroxyphenylacetic acid; VMA: vanillylmandelic acid; Norp: norepinephrine; HAV: Homovanillic acid; GAD1: glutamate decarboxylase 1; GLS: glutaminase; EAAT2: excitatory amino acid transporter 2; VGLUT1: vesicular glutamate transporter 1; SNAT1: sodium-coupled neutral amino acid transporter 1; GLUL: glutamine synthetase; AADC: aromatic-L-amino-acid decarboxylase; TPH1/2: tryptophan 5-hydroxylase ½; MAOA: monoamine oxidase A; SERT: sodium-dependent serotonin transporter; TH: tyrosine 3-hydroxylase; NET: norepinephrine transporter; COMT: catechol O-methyltransferase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase.