title: The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia.
abstract: BACKGROUND
  Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers.
  
  
  METHODS
  We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1), aldolase C (Aldoc), triosephosphate isomerase (Tpi1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), phosphoglycerate mutase 1 (Pgam1), phosphoglycerate kinase 1 (Pgk1) and enolase 2 (Eno2). The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats.
  
  
  RESULTS
  Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls.
  
  
  CONCLUSIONS
  This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.
authors.affiliation: Dept of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QT, UK. dm533@cam.ac.uk
authors.forename: Daniel
authors.initials: D
authors.lastname: Martins-de-Souza
authors.forename: Murtada
authors.initials: M
authors.lastname: Alsaif
authors.forename: Agnes
authors.initials: A
authors.lastname: Ernst
authors.forename: Laura W
authors.initials: LW
authors.lastname: Harris
authors.forename: Nancy
authors.initials: N
authors.lastname: Aerts
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Peeters
authors.forename: Bob
authors.initials: B
authors.lastname: Amess
authors.forename: Hassan
authors.initials: H
authors.lastname: Rahmoune
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
authors.forename: Paul C
authors.initials: PC
authors.lastname: Guest
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D015999:Multivariate Analysis; D010622:Phencyclidine; D010735:Phosphoglycerate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010736:Phosphoglycerate Mutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D012559:Schizophrenia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology*; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D006593:Hexokinase; D010735:Phosphoglycerate Kinase; D005634:Fructose-Bisphosphate Aldolase; D010751:Phosphopyruvate Hydratase; D014305:Triose-Phosphate Isomerase; D010736:Phosphoglycerate Mutase; D010622:Phencyclidine