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Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia

Molecular Psychiatry volume 14, pages 1017–1023 (2009)Cite this article

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 [3H]pirenzepine binding and sequenced the CHRM1 in 80 subjects with schizophrenia and 74 age sex-matched control subjects. Kernel density estimation showed that [3H]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 [3H]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.

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Acknowledgements

We thank Mrs Jacyln Bartlett, Ms Suzette Sheppard and Mr Geoff Pavey for technical assistance; Dr Kenneth Opeskin, Ms Christine Hill, Professor Nick Keks and Professor David Copolov contributed towards collecting the tissue and clinical information relating to this study.

This study was supported in part by grants-in-aid from the National Health and Medical Research Council (Project Grant no. 350344), The Rebecca L Cooper Medical Research Foundation and the Wood's Family Research Program. ES was the Ronald Philip Griffiths Research Fellow and the recipient of a NARSAD 2005 Young Investigator award, She is now the Royce Abbey Post-Doctoral Fellow. BD is an NH&MRC Senior Research Fellow (no.; 400016).

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Authors and Affiliations

  1. Centre for Neuroscience, The University of Melbourne, Parkville, VIC, Australia

    E Scarr

  2. Rebecca L Cooper Research Laboratories, Mental Health Research Institute of Victoria, Parkville, VIC, Australia

    E Scarr & B Dean

  3. Department of Pathology, The University of Melbourne, Parkville, VIC, Australia

    T F Cowie, S Kanellakis & B Dean

  4. NeuroProteomics and NeuroGenomics Platform, The National Neuroscience Facility, Parkville, VIC, Australia

    T F Cowie, S Kanellakis & B Dean

  5. Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia

    S Sundram, C Pantelis & B Dean

  6. Molecular Psychopharmacology, Mental Health Research Institute, Parkville, VIC, Australia

    S Sundram

  7. Northern Psychiatry Research Centre, The Northern Hospital, Epping, VIC, Australia

    S Sundram

  8. Melbourne Neuropsychiatry Centre, The University of Melbourne, Parkville, VIC, Australia

    C Pantelis

  9. Department of Psychological Medicine, Monash University, Clayton, VIC, Australia

    B Dean

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  1. E Scarr
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Correspondence to E Scarr.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Scarr, E., Cowie, T., Kanellakis, S. et al. Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia. Mol Psychiatry 14, 1017–1023 (2009). https://doi.org/10.1038/mp.2008.28

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