title: Decreased cortical muscarinic M1 receptors in schizophrenia are associated with changes in gene promoter methylation, mRNA and gene targeting microRNA.
abstract: Many 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.
authors: Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors: E
authors: E
authors: Scarr
authors: J M
authors: JM
authors: Craig
authors: M J
authors: MJ
authors: Cairns
authors: M S
authors: MS
authors: Seo
authors: J C
authors: JC
authors: Galati
authors: N J
authors: NJ
authors: Beveridge
authors: A
authors: A
authors: Gibbons
authors: S
authors: S
authors: Juzva
authors: B
authors: B
authors: Weinrich
authors: M
authors: M
authors: Parkinson-Bates
authors: A P
authors: AP
authors: Carroll
authors: R
authors: R
authors: Saffery
authors: B
authors: B
authors: Dean
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D018390:Gene Targeting / Q000523:psychology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000172:deficiency / Q000235:genetics*; D012559:Schizophrenia / Q000145:classification / Q000235:genetics* / Q000473:pathology
chemical_list: C086088:CHRM1 protein, human; C549045:MIRN107 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic