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Free keywords:
schizophrenia; MK-801; clozapine; neurons; astrocytes; oligodendrocytes; Western blot; glycolysis
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 (PG,
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.
