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Golgi–Cox staining of dendritic spine subtypes in the orbitofrontal cortex (BA11) and correlation with FKBP5/BDNF gene expression levels analysed with single-nucleus RNA sequencing data derived from the same subjects. a Representative image of a cortical section stained with Golgi-Cox and a stained apical dendrite on a pyramidal neuron. b Classification of different types of dendritic spines: mushroom, stubby, thin and filopodia based on measurements of spine length (base to tip) as well as width (at the widest point) with a photographic example (above) and diagram (below). c Images showing dendritic spine densities in a subject expressing low FKBP5 mRNA levels vs high FKBP5 mRNA levels. Partial correlations accounting for age, PMI and RIN were performed to assess the association between FKBP5 gene expression and d mushroom spine densities and eBDNF gene expression, both showing a strong inverse correlation. fBDNF gene expression and mushroom spine density were strongly positively correlated
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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/pro...
Citations
... Indeed, the hypothesis that stress occurring early in life when the brain is vulnerable is crucial to disorder onset has existed for decades 55-57 sex is likely a strong mediator of these changes 58 . Another study profiling the transcriptome of cortical astrocytes derived from male rodents exposed to chronic variable stress identified upregulation of GRIA2 and GRIA1, in agreement with our glucocorticoid-treated iAsts 59 . The potential of these models to capture these changes at the bulk transcriptome level may also be partly due to their capacity to control the genetic and environmental conditions within the sample, something not possible in human studies. ...
Severe psychological stress is one of the most potent risk factors for developing a mood or psychotic disorder, yet the underlying molecular mechanisms are poorly understood. Astrocytes are a key brain cell type associated with stress and psychiatric phenotypes in animals, but how this translates to humans is largely unknown. Here, we show that cortical astrocytes are persistently changed both physically and molecularly in humans with psychiatric disorders exposed to profound stress before diagnosis. By profiling the diversity of human astrocytes with single nucleus and spatial transcriptomics, we identified distinct alterations to glutamate-related synaptic functions, supported by histological quantification of >20,000 astrocytes. Alterations were pronounced in females compared to males and in cases exposed to profound stress during childhood. The use of human pluripotent stem cell-derived astrocytes confirmed that glutamate signalling is directly impacted by glucocorticoid activation. Our findings suggest that astrocytes are strategic pharmacological targets for future intervention strategies.
... These studies converged with parallel functional analyses of GWAS loci (20,21). Targeted transcriptomic and proteomic postmortem analyses also focused on disease associations with expression of immune-and stress-related genes (22). Single-nucleus RNA sequencing (snRNA-seq) suggested some neuronal and non-neuronal cell types related to risk loci, stress pathways, and/or sex differences (23)(24)(25). ...
The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.
... These studies converged with parallel functional analyses of GWAS loci (20,21). Targeted transcriptomic and proteomic postmortem analyses also focused on disease associations with expression of immune-and stress-related genes (22). Single-nucleus RNA sequencing (snRNA-seq) suggested some neuronal and non-neuronal cell types related to risk loci, stress pathways, and/or sex differences (23)(24)(25). ...
... As previously described 37,38 , ethics approval was obtained from both the Ludwig Maximilians-Universität (22-0523) and the Human Research Ethics Committees at the University of Wollongong (HE2018/351). Donors or their next of kin provided informed consent for brain donation. ...
Psychiatric disorders like schizophrenia, bipolar disorder, and major depressive disorder exhibit significant genetic and clinical overlap. However, their molecular architecture remains elusive due to their polygenic nature and complex brain cell interactions. Here, we integrated clinical data with genetic susceptibility to investigate gene expression and chromatin accessibility in the orbitofrontal cortex of 92 postmortem human brain samples at the single-cell level. Through single-nucleus (sn) RNA-seq and snATAC-seq, we analyzed approximately 800,000 and 400,000 nuclei, respectively. We observed cell type-specific dysregulation related to clinical diagnosis and genetic risk across cortical cell types. Dysregulation in gene expression and chromatin accessibility associated with diagnosis was pronounced in excitatory neurons. Conversely, genetic risk predominantly impacted glial and endothelial cells. Notably, INO80E and HCN2 genes exhibited dysregulation in excitatory neurons superficial layers 2/3 influenced by schizophrenia polygenic risk. This study unveils the complex genetic and epigenetic landscape of psychiatric disorders, emphasizing the importance of cell type-specific analyses in understanding their pathogenesis and contrasting genetic predisposition with clinical diagnosis.
... In animal models, increased FKBP5 activity in specific, mainly limbic, brain regions has been associated with behaviors indicative of increased anxiety and reduced stress coping [37], while blocking of endogenous FKBP51 resulted in opposite behavioral effects [38][39][40]. In postmortem brain, FKBP5 expression is higher in patients with schizophrenia and depression, especially in upper layer excitatory neurons [41] and FKBP51 has been proposed as an interesting drug target for a subset of patients [42]. To followup on this it would be critical to better understand the epigenetic and genetic regulation of the locus in the context of an organism, which would also improve biomarker development of central FKBP5 hyperactivity. ...
... Human postmortem brain tissue: study 3. Postmortem brain tissues from the orbitofrontal cortex (BA 11) for 86 subjects were obtained from the NSW Brain Tissue Resource Centre (University of Sydney, Australia). Tissue was dissected from the 3rd 8-10 mm coronal slice of each fresh-frozen hemisphere (see [41], Table 1 and supplementary methods for detailed cohort description). Informed consent for brain autopsy was provided by the donors or their next of kin. ...
Humanized mouse models can be used to explore human gene regulatory elements (REs), which frequently lie in non-coding and less conserved genomic regions. Epigenetic modifications of gene REs, also in the context of gene x environment interactions, have not yet been explored in humanized mouse models. We applied high-accuracy measurement of DNA methylation (DNAm) via targeted bisulfite sequencing (HAM-TBS) to investigate DNAm in three tissues/brain regions (blood, prefrontal cortex and hippocampus) of mice carrying the human FK506-binding protein 5 (FKBP5) gene, an important candidate gene associated with stress-related psychiatric disorders. We explored DNAm in three functional intronic glucocorticoid-responsive elements (at introns 2, 5, and 7) of FKBP5 at baseline, in cases of differing genotype (rs1360780 single nucleotide polymorphism), and following application of the synthetic glucocorticoid dexamethasone. We compared DNAm patterns in the humanized mouse (N = 58) to those in human peripheral blood (N = 447 and N = 89) and human postmortem brain prefrontal cortex (N = 86). Overall, DNAm patterns in the humanized mouse model seem to recapitulate DNAm patterns observed in human tissue. At baseline, this was to a higher extent in brain tissue. The animal model also recapitulated effects of dexamethasone on DNAm, especially in peripheral blood and to a lesser extent effects of genotype on DNAm. The humanized mouse model could thus assist in reverse translation of human findings in psychiatry that involve genetic and epigenetic regulation in non-coding elements.
... One identified CpG was annotated to FKBP5, a stress-responsive gene and an important regulator of the hypothalamic-pituitaryadrenal (HPA) axis [72]. DNAm in FKBP5 has been robustly linked with early-life adversity and stress-related psychiatric symptoms, such as posttraumatic stress disorder (PTSD) and other anxiety disorders [10,[73][74][75][76], and FKBP5 is also included in gene networks linked to GR signaling and inflammatory response [77]. One CpG identified in PBMCs and one CpG in BECs reside in SLC6A3 encoding dopamine transporter, which has been implicated in a range of psychiatric disorders, including mood disorders, PTSD, schizophrenia, drug addiction, and oppositional defiant disorder in adults [78,79], as well as emotional and behavioral functioning in children [22,42,80,81]. ...
Background: Cumulative family adversity (cumulative FA), characterized by co-occurring stressors in a family context, may be biologically embedded through DNA methylation (DNAm) and contribute to later health outcomes.
Materials & Methods: We compared epigenome-wide DNAm associated with cumulative FA in buccal epithelial cells (BECs; n=218) and peripheral blood mononuclear cells (PBMCs; n=51) from 7-13-year-old children in Canada, accounting for sex, age, predicted cell-type proportion, and genetic ancestry.
Results: Higher levels of cumulative FA were associated with DNAm at seven sites, primarily in stress- and immune-related genes, only in PBMCs. Negative mother-child interaction contributed to this association.
Conclusions: The findings of this study suggested that PBMC DNAm can be used as a marker for biological embedding of cumulative FA.
... FKBP5 has been widely studied in neurological disorders, including post-traumatic stress disorder (PTSD), Alzheimer's disease (AD), and Parkinson's disease (PD) [17,[26][27][28][29]. It has also been reported to contribute to aging-related phenotypes, including cardiovascular risk and heightened in ammation [18, [30][31][32]. However, the contributions and mechanisms of action of FKBP5 in senile osteoporosis, a critical age-related metabolic disease, remain unknown. ...
Senile osteoporosis and associated fractures significantly increase the morbidity and mortality of older people, thus increasing the cost of public health. Further investigations are required to explore the molecular causes of senile osteoporosis. In this study, FKBP5 expression in bone marrow mesenchymal stem cells (BMSCs) increased with age, and the degree of expression was inversely related to the patient's bone mineral density or CT values. Functional studies have validated the regulatory function of FKBP5 in BMSCs osteogenesis differentiation through the canonical WNT/β-catenin signaling pathway by binding to β-catenin and promoting its ubiquitination and degradation. Administration of SAFit2, a selective inhibitor of FKBP5, enhanced bone density in an animal model of senile osteoporosis. These findings suggest that FKBP5 may be a novel target and offer a new perspective on osteoporosis treatment.
... Interestingly, with age, FKBP51 imposes a higher risk on developing stress-related illness. Data from both human and rodent studies demonstrated that epigenetic mechanisms cause an age-dependent elevated Fkbp5 induction (49)(50)(51)(52), resulting in augmented intracellular FKBP51 levels, similar to what has been observed in individuals carrying the FKBP5 psychiatric risk allele (23). Adding to this, knockout (KO) of Fkbp5 in mice had an accumulating antidepressant effect across the lifespan (50). ...
Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (Fkbp5Nex) and GABAergic (Fkbp5Dlx) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.
Exposure to significant levels of stress and trauma throughout life is a leading risk factor for the development of major psychiatric disorders. Despite this, we do not have a comprehensive understanding of the mechanisms that explain how stress raises psychiatric disorder risk. Stress in humans is complex and produces variable molecular outcomes depending on the stress type, timing, and duration. Deciphering how stress increases disorder risk has consequently been challenging to address with the traditional single-target experimental approaches primarily utilized to date. Importantly, the molecular processes that occur following stress are not fully understood but are needed to find novel treatment targets. Sequencing-based omics technologies, allowing for an unbiased investigation of physiological changes induced by stress, are rapidly accelerating our knowledge of the molecular sequelae of stress at a single-cell resolution. Spatial multi-omics technologies are now also emerging, allowing for simultaneous analysis of functional molecular layers, from epigenome to proteome, with anatomical context. The technology has immense potential to transform our understanding of how disorders develop, which we believe will significantly propel our understanding of how specific risk factors, such as stress, contribute to disease course. Here, we provide our perspective of how we believe these technologies will transform our understanding of the neurobiology of stress, and also provided a technical guide to assist molecular psychiatry and stress researchers who wish to implement spatial omics approaches in their own research. Finally, we identify potential future directions using multi-omics technology in stress research.
