Abstract
BackgroundAlthough a number of proteins and genes relevant to schizophrenia have been identified in recent years, few are known about the exact metabolic pathway involved in this disease. Our previous proteomic study has revealed the energy metabolism abnormality in subchronic MK-801 treated rat, a well-established animal model for schizophrenia. This prompted us to further investigate metabolite levels in the same rat model to better delineate the metabolism dysfunctions and provide insights into the pathology of schizophrenia.MethodsMetabolomics, a high-throughput investigatory strategy developed in recent years, can offer comprehensive metabolite-level insights that complement protein and genetic findings. In this study, we employed a nondestructive metabolomic approach (1H-MAS-NMR) to investigate the metabolic traits in cortex and hippocampus of MK-801 treated rats. Multivariate statistics and ingenuity pathways analyses (IPA) were applied in data processing. The result was further integrated with our previous proteomic findings by IPA analysis to obtain a systematic view on our observations.ResultsClear distinctions between the MK-801 treated group and the control group in both cortex and hippocampus were found by OPLS-DA models (with R2X = 0.441, Q2Y = 0.413 and R2X = 0.698, Q2Y = 0.677, respectively). The change of a series of metabolites accounted for the separation, such as glutamate, glutamine, citrate and succinate. Most of these metabolites fell in a pathway characterized by down-regulated glutamate synthesis and disturbed Krebs cycle. IPA analysis further confirmed the involvement of energy metabolism abnormality induced by MK-801 treatment.ConclusionsOur metabolomics findings reveal systematic changes in pathways of glutamate metabolism and Krebs cycle in the MK-801 treated rats’ cortex and hippocampus, which confirmed and improved our previous proteomic observation and served as a valuable reference to the etiology research of schizophrenia.
Highlights
Schizophrenia is a severe and complicated mental disorder that seriously impairs human independence and imposes a significant burden on society [1]
Animal models treated by noncompetitive NMDA receptor antagonists, such as dizocilpine (MK-801) and phencyclidine, are widely used in schizophrenia research [5]
Multivariate Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) analysis was implemented to directly search for treatment related metabolites and the results were displayed in the forms of score plots and back-scaled loadings plots (Figure 2)
Summary
Schizophrenia is a severe and complicated mental disorder that seriously impairs human independence and imposes a significant burden on society [1] Both hereditary and environmental factors contribute to this disease. When the receptor is activated, transcription factors such as CREB (cAMP response element-binding) is mobilized to modulate long-term potentiation, long-term memory, synaptic plasticity and cell survival status. Based on this hypothesis, animal models treated by noncompetitive NMDA receptor antagonists, such as dizocilpine (MK-801) and phencyclidine, are widely used in schizophrenia research [5]. Our previous proteomic study has revealed the energy metabolism abnormality in subchronic MK-801 treated rat, a well-established animal model for schizophrenia. This prompted us to further investigate metabolite levels in the same rat model to better delineate the metabolism dysfunctions and provide insights into the pathology of schizophrenia
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