Abstract
Separate lines of evidence have demonstrated the involvement of N-methyl-D-aspartate (NMDA) receptor and oligodendrocyte dysfunctions in schizophrenia. Here, we have carried out shotgun mass spectrometry proteome analysis of oligodendrocytes treated with the NMDA receptor antagonist MK-801 to gain potential insights into these effects at the molecular level. The MK-801 treatment led to alterations in the levels of 68 proteins, which are associated with seven distinct biological processes. Most of these proteins are involved in energy metabolism and many have been found to be dysregulated in previous proteomic studies of post-mortem brain tissues from schizophrenia patients. Finally, addition of the antipsychotic clozapine to MK-801-treated oligodendrocyte cultures resulted in changes in the levels of 45 proteins and treatment with clozapine alone altered 122 proteins and many of these showed opposite changes to the MK-801 effects. Therefore, these proteins and the associated energy metabolism pathways should be explored as potential biomarkers of antipsychotic efficacy. In conclusion, MK-801 treatment of oligodendrocytes may provide a useful model for testing the efficacy of novel treatment approaches.
Highlights
The N-methyl-D-aspartate receptor (NMDAr) is an ionotropic receptor activated by glutamate, allowing the non-selective influx of calcium and sodium and outflow of potassium
The development of new preclinical models to improve such knowledge is challenging for the same reasons
Biological assays using animals or cellular cultures as models are still emerging, with the aim to provide more information about the acute effects caused by administration of neuromodulators such as MK-801 and antipsychotic drugs (Paulson et al, 2004, 2007; Ji et al, 2009a,b; Ma et al, 2009; Martins-de-Souza et al, 2011b; Ahmed et al, 2012; Palmowski et al, 2014)
Summary
The N-methyl-D-aspartate receptor (NMDAr) is an ionotropic receptor activated by glutamate, allowing the non-selective influx of calcium and sodium and outflow of potassium. While NMDAr function has been well-described in neurons, its function in glial cells such as astrocytes and oligodendrocytes still needs clarification despite intensive investigation over the past 10 years (Salter and Fern, 2005; Cao and Yao, 2013). This is likely to provide further insights into the pathways affected in schizophrenia, given the role of oligodendrocytes in the establishment and course of the disease (Cassoli et al, 2015). The main objective was to shed light on the biochemical mechanisms involving NMDAr function in oligodendrocytes in order to determine whether these cells could be useful in future studies to model some aspects of schizophrenia
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