title: MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia.
abstract: Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes, and oligodendrocytes are affected differently in schizophrenia. Employing in vitro models using neurotransmitter agonists and antagonists may provide new insights about the pathophysiology of schizophrenia which could lead to a novel system for drug discovery.
authors.affiliation: Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas Campinas, Brazil.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Guest
authors.affiliation: Research Center for Child Mental Development, University of Fukui Fukui, Japan ; Department of Development of Functional Brain Activities, United Graduate School of Child Development, Osaka University-Kanazawa University-Hamamatsu University School of Medicine-Chiba University-University of Fukui Fukui, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwata
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan ; Innovation Center for Medical Redox Navigation, Kyushu University Fukuoka, Japan.
authors.forename: Takahiro A
authors.initials: TA
authors.lastname: Kato
authors.affiliation: Department of Psychiatry and Psychotherapy-Center for Behavioral Brain Sciences, University of Magdeburg Magdeburg, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Steiner
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University Munich, Germany ; Laboratory of Neurosciences (LIM-27), Institute of Psychiatry, University of São Paulo São Paulo, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Department of Translational Research in Psychiatry Proteomics and Biomarkers, Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas Campinas, Brazil ; Laboratory of Neurosciences (LIM-27), Institute of Psychiatry, University of São Paulo São Paulo, Brazil ; UNICAMP's Neurobiology Center Campinas, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martins-de-Souza
keywords: MK-801; Western blot; astrocytes; clozapine; glycolysis; neurons; oligodendrocytes; schizophrenia