Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex.
Natalie Matosin, Janine Arloth, Darina Czamara, Katrina Z Edmond, Malosree Maitra, Anna S Fröhlich, Silvia Martinelli, Dominic Kaul, Rachael Bartlett, Amber R Curry, Nils C Gassen, Kathrin Hafner, Nikola S Müller, Karolina Worf, Ghalia Rehawi, Corina Nagy, Thorhildur Halldorsdottir, Cristiana Cruceanu, Miriam Gagliardi, Nathalie Gerstner, Maik Ködel, Vanessa Murek, Michael J Ziller, Elizabeth Scarr, Ran Tao, Andrew E Jaffe, Thomas Arzberger, Peter Falkai, Joel E Kleinmann, Daniel R Weinberger, Naguib Mechawar, Andrea Schmitt, Brian Dean, Gustavo Turecki, Thomas M Hyde, Elisabeth B Binder
Author Information
Natalie Matosin: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany. nmatosin@uow.edu.au. ORCID
Janine Arloth: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Darina Czamara: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Katrina Z Edmond: Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia.
Malosree Maitra: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, Canada.
Anna S Fröhlich: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Silvia Martinelli: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Dominic Kaul: Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia.
Rachael Bartlett: Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia.
Amber R Curry: Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia.
Nils C Gassen: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Kathrin Hafner: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Nikola S Müller: Institute of Computational Biology, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
Karolina Worf: Institute of Computational Biology, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
Ghalia Rehawi: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Corina Nagy: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, Canada.
Thorhildur Halldorsdottir: Department of Psychology, Reykjavik University, Reykjavik, Iceland.
Cristiana Cruceanu: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Miriam Gagliardi: Department of Psychiatry, University of Münster, Münster, Germany.
Nathalie Gerstner: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Maik Ködel: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Vanessa Murek: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Michael J Ziller: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Elizabeth Scarr: Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Ran Tao: The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Andrew E Jaffe: The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Thomas Arzberger: Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University Munich, Nussbaumstrasse 7, 80336, Munich, Germany.
Peter Falkai: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
Joel E Kleinmann: The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Daniel R Weinberger: The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Naguib Mechawar: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, Canada.
Andrea Schmitt: Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University Munich, Nussbaumstrasse 7, 80336, Munich, Germany.
Brian Dean: Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Gustavo Turecki: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, Canada.
Thomas M Hyde: The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Elisabeth B Binder: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany. binder@psych.mpg.de.
Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.
