Chronic Stress in a Rat Model of Depression Disturbs the Glutamine–Glutamate–GABA Cycle in the Striatum, Hippocampus, and Cerebellum

Abstract

Shaohua Xu, 1–3,* Yiyun Liu, 2, 3,* Juncai Pu, 2, 3,* Siwen Gui, 2–4,* Xiaogang Zhong, 2, 3 Lu Tian, 2, 3 Xuemian Song, 2–4 Xunzhong Qi, 2, 3 Haiyang Wang, 2, 3 Peng Xie 1–3, 5 1Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, People’s Republic of China; 2NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 3Chongqing Key Laboratory of Neurobiology, Chongqing 400016, People’s Republic of China; 4College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng XieNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: Major depressive disorder (MDD) is a complex psychiatric illness involving multiple brain regions. Increasing evidence indicates that the striatum is involved in depression, but the molecular mechanisms remain unclear.Methods: In this study, we performed a gas chromatography–mass spectrometer (GC/MS)-based metabolomic analysis in the striatum of depressed rats induced by chronic unpredictable mild stress (CUMS). We then compared striatal data with our previous data from the hippocampus and cerebellum to systematically investigate the potential pathogenesis of depression.Results: We identified 22 differential metabolites in the striatum between the CUMS and control groups; these altered metabolites were mainly involved in amino acid, carbohydrate, and nucleotide metabolism. Pathway analysis revealed that the shared metabolic pathways of the striatum, hippocampus, and cerebellum were mainly involved in the glutamine–glutamate metabolic system. Four genes in the striatum (GS, GLS2, GLT1, and SSADH), six genes in the hippocampus (GS, SNAT1, GAD1, SSADH, VGAT, and ABAT), and five genes in the cerebellum (GS, ABAT, SNAT1, VGAT, and GDH) were found to be significantly altered using RT-qPCR. Correlation analysis indicated that these differential genes were strongly correlated.Conclusion: These results suggest that chronic stress might induce depressive behaviors by disturbing the glutamine–glutamate–GABA cycle in the striatum, hippocampus, and cerebellum, and that the glutamine–glutamate–GABA cycle among these three brain regions might generate cooperative action in response to chronic stress.Keywords: chronic unpredictable mild stress, glutamine–glutamate–GABA cycle, depression, striatum, GC/MS

Keywords

• chronic unpredictable mild stress
• glutamine–glutamate–gaba cycle
• depression
• striatum
• gc/ms