craig-decreasedcortical-2013.pdf (900.03 kB)
Decreased cortical muscarinic M1 receptors in schizophrenia are associated with changes in gene promoter methylation, mRNA and gene targeting microRNA
journal contribution
posted on 2013-02-19, 00:00 authored by E Scarr, Jeffrey CraigJeffrey Craig, M J Cairns, M S Seo, J C Galati, N J Beveridge, A Gibbons, S Juzva, B Weinrich, M Parkinson-Bates, A P Carroll, R Saffery, B DeanMany studies have shown decreased cortical muscarinic M1 receptors (CHRM1) in schizophrenia (Sz), with one study showing Sz can be separated into two populations based on a marked loss of CHRM1 (-75%) in -25% of people (Def-Sz) with the disorder. To better understand the mechanism contributing to the loss of CHRM1 in Def-Sz, we measured specific markers of gene expression in the cortex of people with Sz as a whole, people differentiated into Def-Sz and people with Sz that do not have a deficit in cortical CHRM1 (Non-Def-Sz) and health controls. We now report that cortical CHRM1 gene promoter methylation and CHRM1 mRNA are decrease in Sz, Def-Sz and Non-Def-Sz but levels of the micro RNA (miR)-107, a CHRM1 targeting miR, are increased only in Def-Sz. We also report in vitro data strongly supporting the notion that miR-107 levels regulate CHRM1 expression. These data suggest there is a reversal of the expected inverse relationship between gene promoter methylation and CHRM1 mRNA in people with Sz and that a breakdown in gene promoter methylation control of CHRM1 expression is contributing to the global pathophysiology of the syndrome. In addition, our data argues that increased levels of at least one miR, miR-107, is contributing to the marked loss of cortical CHRM1 in Def-Sz and this may be a differentiating pathophysiology. These latter data continue to support the hypothesis that microRNAs (miRNA) have a role in the underlying neurobiology of Sz but argue they are differentially affected in subsets of people within that syndrome.
History
Journal
Translational psychiatryVolume
3Article number
e230Pagination
1 - 9Publisher
NatureLocation
London, Eng.Publisher DOI
Link to full text
eISSN
2158-3188Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2013, Macmillan PublishersUsage metrics
Categories
No categories selectedKeywords
AdultCerebral CortexCohort StudiesDNA MethylationFemaleGene Expression RegulationGene TargetingHumansMaleMicroRNAsMiddle AgedPromoter Regions, GeneticRNA, MessengerReceptor, Muscarinic M1Receptors, MuscarinicSchizophreniaScience & TechnologyLife Sciences & BiomedicinePsychiatrycortexCHRM1muscarinic M1 receptorpostmortem CNSDORSOLATERAL PREFRONTAL CORTEXEXPRESSIONBINDINGTISSUEBRAINDIAGNOSISPATHOLOGY
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC