Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex

Authors

Natalie Matosin, Max Planck Institute of Psychiatry
Janine Arloth, Max Planck Institute of Psychiatry
Darina Czamara, Max Planck Institute of Psychiatry
Katrina Z. Edmond, Faculty of Science, Medicine and Health
Malosree Maitra, Le Centre de Recherche Douglas
Anna S. Fröhlich, Max Planck Institute of Psychiatry
Silvia Martinelli, Max Planck Institute of Psychiatry
Dominic Kaul, Faculty of Science, Medicine and Health
Rachael Bartlett, Faculty of Science, Medicine and Health
Amber R. Curry, Faculty of Science, Medicine and Health
Nils C. Gassen, Max Planck Institute of Psychiatry
Kathrin Hafner, Max Planck Institute of Psychiatry
Nikola S. Müller, Helmholtz Center Munich German Research Center for Environmental Health
Karolina Worf, Helmholtz Center Munich German Research Center for Environmental Health
Ghalia Rehawi, Max Planck Institute of Psychiatry
Corina Nagy, Le Centre de Recherche Douglas
Thorhildur Halldorsdottir, Reykjavik University
Cristiana Cruceanu, Max Planck Institute of Psychiatry
Miriam Gagliardi, Westfälische Wilhelms-Universität Münster
Nathalie Gerstner, Max Planck Institute of Psychiatry
Maik Ködel, Max Planck Institute of Psychiatry
Vanessa Murek, Max Planck Institute of Psychiatry
Michael J. Ziller, Max Planck Institute of Psychiatry
Elizabeth Scarr, Faculty of Veterinary and Agricultural Sciences
Ran Tao, Johns Hopkins University
Andrew E. Jaffe, Johns Hopkins University
Thomas Arzberger, Klinikum der Universität München
Peter Falkai, Max Planck Institute of Psychiatry
Joel E. Kleinmann, Johns Hopkins University

Publication Name

Acta Neuropathologica

Abstract

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.

Open Access Status

This publication may be available as open access

Funding Number

NIAAA012725-15

Funding Sponsor

National Institutes of Health

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Link to publisher version (DOI)

http://dx.doi.org/10.1007/s00401-023-02541-9