Abstract
Schizophrenia is a psychotic disorder with severe and disabling symptoms, such as hallucinations, delusions, blunted affect and social withdrawal. The neuropathology remains elusive, but disturbances in immunity-related processes, neuronal connectivity and myelination have consistently been linked to schizophrenia. Antipsychotic drugs can be efficient in reducing symptoms, acting primarily on the dopamine system, but additional biological targets are likely to exist. Here we have screened for novel mechanisms of action in an animal model, using adult rats exposed to long-acting olanzapine, achieving stable and clinically relevant antipsychotic drug concentrations. By microarray-based examination of global gene expression in the fronto-medial cortex, at the single gene- and gene-set level, we observed downregulation of two neuropeptide-encoding genes, Vgf and Cort (fold change −1,25 and −1,48, respectively) in response to olanzapine exposure. Furthermore, we demonstrated significant upregulation of five out of ~2000 GO predefined gene sets after olanzapine exposure. Strikingly, all were linked to myelination and oligodendrocyte development; “Ensheathment of neurons”, “Axon ensheathment”, “Myelination”, “Myelin sheath” and “Oligodendrocyte development” (FDR-values < 25). Sixteen of the leading edge genes in these gene sets were analysed independently by qPCR, of which 11 genes displayed significant upregulation, including Plp1, Mal, Mag and Cnp (fold change: 1,30, 1,50, 1,30 and 1,15, respectively). Several of the upregulated genes (e.g. MAG, MAL and CNP) have previously been reported as downregulated in post-mortem brain samples from schizophrenia patients. Although caution needs to be taken when extrapolating results from animal studies to humans, the data suggest a role for olanzapine in alleviating myelination-related dysfunction in schizophrenia.
Highlights
Schizophrenia is a disabling psychiatric disorder with a lifetime prevalence of about 0.7%1
A marked upregulation of genes linked to oligodendrocytes and myelination processes was identified, in addition to changes in two neuropeptide-encoding genes
Of the ~2000 Gene Ontology (GO) predefined gene sets analysed by GSEA, we observed an upregulation of five gene sets, all of which were linked to oligodendrocyte development and myelination
Summary
Schizophrenia is a disabling psychiatric disorder with a lifetime prevalence of about 0.7%1. As an alternative approach to study the pathological disease mechanisms, large-scale gene expression studies have been performed on post-mortem brain samples from patients suffering from schizophrenia. The most consistent observations from these studies include alterations in expression levels for genes related to brain white matter and oligodendrocytes, signalling and synapses, GABA and glutamate neurotransmission, mitochondrial function, in Ersland et al Translational Psychiatry (2017)7:1262 addition to immune and stress-response (reviewed in[9,10,11]). Several studies have reported a downregulation of genes linked to myelination and myelinproducing oligodendrocytes in schizophrenia[12,13,14,15,16]. Oligodendrocyte membranes wrap around axons forming a multi-lamellar myelin structure, which is essential for rapid propagation of action potentials and the long-term integrity of neuronal axons. Since myelin is a lipid-rich membrane structure, it is interesting that several antipsychotic drugs, especially clozapine and olanzapine, have been shown to have lipid-stimulating effects
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