Associations of psychiatric disease and aging on FKBP5 expression converge on cortical supragranular neurons

Natalie Matosin; Janine Arloth; Darina Czamara; Katrina Z. Edmond; Malosree Maitra; Anna Sophie 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. Kleinman; Daniel R. Weinberger

doi:10.1101/2021.01.27.428487

NeurosciencebioRxivJan 27, 2021

Preprint

Associations of psychiatric disease and aging on FKBP5 expression converge on cortical supragranular neurons

Natalie Matosin iD, Janine Arloth iD, Darina Czamara iD, Katrina Z. Edmond iD, Malosree Maitra, Anna Sophie Fröhlich iD, Silvia Martinelli iD, Dominic Kaul iD, Rachael Bartlett iD, Amber R. Curry, Nils C. Gassen iD, Kathrin Hafner, Nikola S. Müller iD, Karolina Worf iD, Ghalia Rehawi iD, Corina Nagy iD, Thorhildur Halldorsdottir iD, Cristiana Cruceanu iD, Miriam Gagliardi iD, Nathalie Gerstner iD, Maik Ködel, Vanessa Murek iD, Michael J. Ziller iD, Elizabeth Scarr iD, Ran Tao, , Elisabeth B. Binder iD

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 prefrontal cortex (BA9, BA11, BA24) 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, aging 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) and targeted histology, we established that these disease- and aging-effects on FKBP5/1 expression were most pronounced in excitatory supragranular neurons. We then found that this increase in FKBP5 levels likely impacts on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in supragranular neurons. These findings pinpoint a novel cellular and molecular mechanism that has significant potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.

PDF DOI