Low levels of muscarinic M1 receptor–positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia

Low levels of muscarinic M1 receptor–positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia

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J Psychiatry Neurosci 2018;43(5):338-346

Elizabeth Scarr, PhD; Shaun Hopper, MSc; Valentina Vos, BSc (Hons); Myoung Suk Seo, PhD; Ian Paul Everall, MBChB (Hons), PhD, DSc; Timothy Douglas Aumann, PhD; Gursharan Chana, MSc, PhD; Brian Dean, MSc, PhD

Abstract

Background: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of muscarinic M1 receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low receptor levels.

Methods: We determined the distribution and number of CHRM1- positive (CHRM1+) neurons in the cortex, medial dorsal nucleus of the thalamus and regions of the hippocampus from controls (n = 12, 12 and 5, respectively) and people with schizophrenia (n = 24, 24 and 13, respectively).

Results: Compared with controls, levels of CHRM1+ neurons in people with schizophrenia were lower on pyramidal cells in layer III of Brodmann areas 9 (−44%) and 17 (−45%), and in layer V in Brodmann areas 9 (−45%) and 17 (−62%). We found no significant differences in the number of CHRM1+ neurons in the medial dorsal nucleus of the thalamus or in the hippocampus.

Limitations: Although diagnostic cohort sizes were typical for this type of study, they were relatively small. As well, people with schizophrenia were treated with antipsychotic drugs before death.

Conclusion: The loss of CHRM1+ pyramidal cells in the cortex of people with schizophrenia may underpin derangements in the cholinergic regulation of GABA-ergic activity in cortical layer III and in cortical/subcortical communication via pyramidal cells in layer V.


Submitted Oct. 19, 2017; Revised Nov. 28, 2017; Revised Dec. 19, 2017; Revised Dec. 20, 2017; Accepted Jan. 4, 2018; Published online first May 31, 2018

Acknowledgments: The authors thank the staff of the Victorian Brain Bank Network and the Advanced Microscopy Facility, the Florey, for their support. Tissues were received from the Victorian Brain Bank Network, supported by the Florey, the Alfred Hospital and the Victorian Institute for Forensic Medicine. This work was supported by the National Medical and Health Research Council (grants APP1048544, APP1045619, APP1002240 and APP1037234), the Australian Research Council (grants DP110100086 and FT100100689), the Andrew and Claire Henna Ride for Ben, One in Five and the Operation Infrastructure Support Grant from the Victorian State Government.

Affiliations: From the Molecular Psychiatry Laboratory, University of Melbourne, Victoria, Australia (Scarr, Hopper, Vos, Suk Seo, Dean); the Midbrain Dopamine Plasticity Laboratory, the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia (Aumann); the Centre for Mental Health, Faculty of Health, Arts and Design, Swinburne University, Victoria, Australia (Dean); the Department of Psychiatry, University of Melbourne, Victoria, Australia (Everall); the Integrative Biological Psychiatry Laboratory, Centre for Neural Engineering, University of Melbourne, Victoria, Australia (Chana); and the Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Victoria, Australia (Scarr).

Competing interests: None declared.

Contributors: E. Scarr, I. Everall, T. Aumann, G. Chana and B. Dean designed the study. E. Scarr, S. Hopper, V. Vos and M. Seo acquired and analyzed the data, which B. Dean also analyzed. B. Dean wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170202

Correspondence to: B. Dean, The Molecular Psychiatry Laboratories, The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3010, Australia; brian.dean@florey.edu.au