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.
Highlights
Schizophrenia is a severe, debilitating mental disorder that directly affects more than 30 million people worldwide (van Os and Kapur, 2009)
Effects of Treatment of Cultured Cells with MK-801 and Clozapine HT22 Neuronal Cells Acute treatment of HT22 cells led to significantly increased levels of hexokinase 1 (HK1) and phosphoglycerate mutase 1 (PGAM1), as determined by analysis of variance (ANOVA) (Table 1; see Supplementary Figure S1 for Western blot images of the immunoreactive protein bands for each enzyme under acute and long term conditions in the three cell types)
This suggests that astrocytes and neuronal cells are either more resistant to the stresses induced by MK-801 treatment or that oligodendrocytes are more susceptible to treatment with this reagent
Summary
Schizophrenia is a severe, debilitating mental disorder that directly affects more than 30 million people worldwide (van Os and Kapur, 2009). The current diagnosis is interview-based and involves communication of subjective symptoms, emotions, and histories between the patient and physician, and categorization of patients is performed using the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) or the International Statistical Classification of Diseases and Related Health Problems 10th revision (WHO, 2010; American Psychiatric Association, 2013). The changes in these proteins suggest that there is net effect on loss of myelination and synaptic function, leading to dysfunction of specific brain areas, and perturbed networking across distal brain regions (Stephan et al, 2009; Martins-de-Souza, 2010)
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