title: Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model.
abstract: Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic approaches to treat schizophrenia fail to address all symptomatic manifestations of the disease. Therefore, disease models that reproduce core pathological features of schizophrenia are needed for the elucidation of pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatography-mass spectrometry proteomic (LC-MS(E)) and metabonomic (LC-MS) profiling analysis combined with the targeted proteomics (selected reaction monitoring and multiplex immunoassay) of serum and brain tissues to investigate a chronic phencyclidine (PCP) rat model in which glutamatergic hypofunction is induced through noncompetitive NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified alterations in the levels of several cytokines (IL-5, IL-2, and IL-1β) and fibroblast growth factor-2. Extensive proteomic and metabonomic brain tissue profiling revealed a more prominent effect of chronic PCP treatment on both the hippocampal proteome and metabonome compared to the effect on the frontal cortex. Bioinformatic pathway analysis confirmed prominent abnormalities in NMDA-receptor-associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA, and GABAergic signaling in the hippocampus and in proteins associated with neurodegeneration. We further identified abundance changes in the level of the superoxide dismutase enzyme (SODC) in both the frontal cortex and hippocampus, which indicates alterations in oxidative stress and substantiates the apoptotic pathway alterations. The present study could lead to an increased understanding of how perturbed glutamate receptor signaling affects other relevant biological pathways in schizophrenia and, therefore, support drug discovery efforts for the improved treatment of patients suffering from this debilitating psychiatric disorder.
authors.affiliation: †Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, U.K.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Wesseling
authors.affiliation: ‡Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London SW7 2AZ, U.K.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Want
authors.affiliation: †Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, U.K.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Guest
authors.affiliation: †Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, U.K.
authors.forename: Hassan
authors.initials: H
authors.lastname: Rahmoune
authors.affiliation: ‡Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London SW7 2AZ, U.K.
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.affiliation: †Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, U.K.|§Department of Neuroscience, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002853:Chromatography, Liquid; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006213:Hallucinogens / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics / Q000379:methods*; D018384:Oxidative Stress / Q000187:drug effects*; D010622:Phencyclidine / Q000633:toxicity*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D016207:Cytokines; D006213:Hallucinogens; D020543:Proteome; D013482:Superoxide Dismutase; D010622:Phencyclidine
keywords: LC−MSE; SRM; chronic phencyclidine (PCP) rat model; metabonomics; multiplex immunoassay; proteomics; schizophrenia