title: Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia.
abstract: Schizophrenia is widely acknowledged as being a syndrome, consisting of an undefined number of diseases probably with differing pathologies. Although studying a syndrome makes the identification of an underlying pathology more difficult; neuroimaging, neuropsychopharmacological and post-mortem brain studies all implicate muscarinic acetylcholine receptors (CHRM) in the pathology of the disorder. We have established that the CHRM1 is selectively decreased in the dorsolateral prefrontal cortex of subjects with schizophrenia. To expand this finding, we wanted to ascertain whether decreased cortical CHRMs might (1) define a subgroup of schizophrenia and/or (2) be related to CHRM1 genotype. We assessed cortical [(3)H]pirenzepine binding and sequenced the CHRM1 in 80 subjects with schizophrenia and 74 age sex-matched control subjects. Kernel density estimation showed that [(3)H]pirenzepine binding in BA9 divided the schizophrenia, but not control, cohort into two distinct populations. One of the schizophrenia cohorts, comprising 26% of all subjects with the disorder, had a 74% reduction in mean cortical [(3)H]pirenzepine binding compared to controls. We suggest that these individuals make up 'muscarinic receptor-deficit schizophrenia' (MRDS). The MRDS could not be separated from other subjects with schizophrenia by CHRM1 sequence, gender, age, suicide, duration of illness or any particular drug treatment. Being able to define a subgroup within schizophrenia using a central biological parameter is a pivotal step towards understanding the biochemistry underlying at least one form of the disorder and may represent a biomarker that can be used in neuroimaging.
authors.affiliation: Centre for Neuroscience, The University of Melbourne, Parkville, VIC, Australia. elscarr@unimelb.edu.au
authors.forename: E
authors.initials: E
authors.lastname: Scarr
authors.forename: T F
authors.initials: TF
authors.lastname: Cowie
authors.forename: S
authors.initials: S
authors.lastname: Kanellakis
authors.forename: S
authors.initials: S
authors.lastname: Sundram
authors.forename: C
authors.initials: C
authors.lastname: Pantelis
authors.forename: B
authors.initials: B
authors.lastname: Dean
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D015331:Cohort Studies; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000378:metabolism / Q000494:pharmacology; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000145:classification* / Q000378:metabolism / Q000473:pathology*; D014316:Tritium / Q000378:metabolism
chemical_list: D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D014316:Tritium; D010890:Pirenzepine