title: An investigation of the factors that regulate muscarinic receptor expression in schizophrenia.
abstract: We previously identified a group of subjects with schizophrenia who, on average, have a 75% decrease in cholinergic receptor, muscarinic 1 (CHRM1) in Brodmann's area (BA) 9. To extend this finding, we determined i) if the decrease in CHRM1 was present in another functionally related CNS region (BA6), ii) whether the marked decrease in CHRM1 was accompanied by changes in levels of other CHRMs and iii) potential factors responsible for the decreased CHRM1 expression. We measured CHRM1 and CHRM3 using in situ radioligand binding with [(3)H]pirenzepine and [(3)H]4-DAMP respectively in BA6 from 20 subjects with schizophrenia who had low levels of CHRM1 in BA9 (SzLow[(3)H]PZP), 18 subjects with schizophrenia whose levels of CHRM1 were similar to controls (SzNormal[(3)H]PZP) and 20 control subjects. Levels of CHRM1, 3 and 4 mRNA were measured using qPCR and levels of the transcription factors, SP1 and SP3, were determined using Western blots. In BA6, the density of [(3)H]pirenzepine binding was decreased in subjects with SzLow[(3)H]PZP (p<0.001) compared to controls. The density of [(3)H]4-DAMP binding, levels of CHRM1, 3 and 4 mRNA and levels of SP1 and SP3 was not significantly different between the three groups. This study shows that the previously identified decrease in CHRM1 expression is not confined to the dorsolateral prefrontal cortex but is present in other cortical areas. The effect shows some specificity to CHRM1, with no change in levels of binding to CHRM3. Furthermore, this decrease in CHRM1 does not appear to be associated with low levels of CHRM1 mRNA or to simply be regulated by the transcription factors, SP1 and SP3, suggesting that other mechanisms are responsible for the decreased CHRM1 in these subjects.
authors.affiliation: The Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia; Department of Psychiatry, The University of Melbourne Parkville, Victoria 3010, Australia. Electronic address: myoung.seo@florey.edu.au.
authors.forename: Myoung Suk
authors.initials: MS
authors.lastname: Seo
authors.affiliation: The Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia; Department of Psychiatry, The University of Melbourne Parkville, Victoria 3010, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scarr
authors.affiliation: The Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia; Department of Psychiatry, The University of Melbourne Parkville, Victoria 3010, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
mesh_terms: D000328:Adult; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D015331:Cohort Studies; D006801:Humans; D008875:Middle Aged; D010880:Piperidines; D010890:Pirenzepine; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism*; D014316:Tritium
chemical_list: C086088:CHRM1 protein, human; C000595896:CHRM3 protein, human; C000597933:CHRM4 protein, human; D010880:Piperidines; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D014316:Tritium; D051705:Sp3 Transcription Factor; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium
keywords: CHRM1; Cortex; Human; Post-mortem; SP1; Schizophrenia