Combined Metabolomics and Proteomics Analysis of Major Depression in an Animal Model: Perturbed Energy Metabolism in the Chronic Mild Stressed Rat Cerebellum

Abstract

Major depressive disorder (MDD) is a highly prevalent, debilitating mental illness of importance for global health. However, its molecular pathophysiology remains poorly understood. Combined proteomics and metabolomics approaches should provide a comprehensive understanding of MDD's etiology. The present study reports novel ''-omics'' insights from a rodent model of MDD. Cerebellar samples from chronic mild stressed (CMS)-treated depressed rats and controls were compared with a focus on the differentially expressed proteins and metabolites using isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and gas chromotography/mass spectrometry (GC-MS) metabolomics techniques, respectively. The combined analyses found significant alterations associated with cerebellar energy metabolism, as indicated by (1) abnormal amino acid metabolism accompanied by corresponding metabolic enzymatic alterations and disturbed protein turnover, (2) increased glycolytic and tricarboxylic acid (TCA) cycle enzyme levels paralleled by changes in the concentrations of associated metabolites, and (3) perturbation of ATP biosynthesis through adenosine accompanied by perturbation of the mitochondrial respiratory chain. To the best of our knowledge, this study is the first to integrate proteomics and metabolomics analyses to examine the pathophysiological mechanism(s) underlying MDD in a CMS rodent model of depression. These results can offer important insights into the pathogenesis of MDD.

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

“…21,22 Based on metabolomics technology, our previous studies found both a disturbance in energy metabolism in the cerebellum and a dysfunction of amino acid and lipid metabolism in the hippocampus of CUMS model rats. 23,24 These preliminary findings suggest that depression involves metabolic alterations in multiple brain regions. However, previous studies have mostly focused on a single brain region, thus ignoring the systemic metabolic alterations that occur in multiple brain regions during the pathology of depression.…”

Novel urinary metabolite signature for diagnosing postpartum depression

“…Currently, metabolomics and other methods have been developed to identify the potential biomarkers for neuropsychiatric disorders,13,14 including depression, bipolar disorder and schizophrenia 15–17. Through metabolomics, previous studies found that there were urinary metabolic abnormalities in patients with MDD 15,18.…”

Alteration of Energy Metabolism and Antioxidative Processing in the Hippocampus of Rats Reared in Long-Term Environmental Enrichment

“…Adenylate kinase 1 maintains the balance between ATP consumption and production by catalyzing the reversible phosphotransfer between ADP, ATP and AMP [30]. A literature search indicated that energy metabolism-related proteins were decreased in positively stimulating conditions, while they increased in stressful conditions or mental disorders [31,32,33,34]. In support of our results, two interesting studies showed that a lower level of brain activation was observed in EE animals following an anxiety-inducing task [35,36].…”