title: Metabolomic analysis reveals metabolic disturbance in the cortex and hippocampus of subchronic MK-801 treated rats.
abstract: BACKGROUND
  Although 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.
  
  
  METHODS
  Metabolomics, 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.
  
  
  RESULTS
  Clear distinctions between the MK-801 treated group and the control group in both cortex and hippocampus were found by OPLS-DA models (with R(2)X = 0.441, Q(2)Y = 0.413 and R(2)X = 0.698, Q(2)Y = 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, PR China.
authors.forename: Liya
authors.initials: L
authors.lastname: Sun
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhou
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Jinglei
authors.initials: J
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Baohu
authors.initials: B
authors.lastname: Ji
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.forename: Lun
authors.initials: L
authors.lastname: Yang
authors.forename: Guang
authors.initials: G
authors.lastname: He
authors.forename: Linghan
authors.initials: L
authors.lastname: Gao
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.forename: Kejian
authors.initials: K
authors.lastname: Wang
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.forename: Weiqing
authors.initials: W
authors.lastname: Liu
authors.forename: Liwen
authors.initials: L
authors.lastname: Tan
authors.forename: Yihua
authors.initials: Y
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Chunling
authors.initials: C
authors.lastname: Wan
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D055432:Metabolomics; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate