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

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. ### Competing Interest Statement Dr Binder is co-inventor on the following patent applications: FKBP5: a novel target for antidepressant therapy. European Patent # EP1687443 B1; Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments. United States Patent # 8030033; Means and methods for diagnosing predisposition for treatment emergent suicidal ideation (TESI). European application number: 08016477.5, international application number: PCT/EP2009/061575. Dr Falkai has been an honorary speaker for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Essex, GE Healthcare, GlaxoSmithKline, Janssen Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Takeda. During the past 5 years, but not presently, Dr Falkai has been a member of the advisory boards of Janssen-Cilag, AstraZeneca, Eli Lilly, and Lundbeck. Dr Schmitt has been an honorary speaker for TAD Pharma and Roche and has been a member of advisory boards for Roche. The remaining authors declare no competing interests or conflicts of interest.