Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Significance

The FKBP5 gene is a key genetic risk factor for stress-related disorders. The highly divergent symptomology of psychiatric disorders highlights that genetic risk factors like FKBP5 do not simply affect stress-coping mechanisms in a unilateral manner. Rather, we here demonstrate that FKBP5 affects cognitive and emotional behavior, brain structure, and brain region-specific gene expression profiles in a highly cell-type and sex-specific manner. Our results underline that labelling a stress—sensitive factor as FKBP5 as “risk factor” is too simplistic, as loss of FKBP5 can have opposite effects on brain and behavior, dependent on which cell type and sex the loss is taking place. The results are of high importance for the development of targeted intervention strategies for psychiatric disorders.

Abstract

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 ( Fkbp5 ^Nex ) and GABAergic ( Fkbp5 ^Dlx ) 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.

Related collections

Most cited references 89

Record: found
Abstract: found
Article: not found

Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic

(2021)

Background Before 2020, mental disorders were leading causes of the global health-related burden, with depressive and anxiety disorders being leading contributors to this burden. The emergence of the COVID-19 pandemic has created an environment where many determinants of poor mental health are exacerbated. The need for up-to-date information on the mental health impacts of COVID-19 in a way that informs health system responses is imperative. In this study, we aimed to quantify the impact of the COVID-19 pandemic on the prevalence and burden of major depressive disorder and anxiety disorders globally in 2020. Methods We conducted a systematic review of data reporting the prevalence of major depressive disorder and anxiety disorders during the COVID-19 pandemic and published between Jan 1, 2020, and Jan 29, 2021. We searched PubMed, Google Scholar, preprint servers, grey literature sources, and consulted experts. Eligible studies reported prevalence of depressive or anxiety disorders that were representative of the general population during the COVID-19 pandemic and had a pre-pandemic baseline. We used the assembled data in a meta-regression to estimate change in the prevalence of major depressive disorder and anxiety disorders between pre-pandemic and mid-pandemic (using periods as defined by each study) via COVID-19 impact indicators (human mobility, daily SARS-CoV-2 infection rate, and daily excess mortality rate). We then used this model to estimate the change from pre-pandemic prevalence (estimated using Disease Modelling Meta-Regression version 2.1 [known as DisMod-MR 2.1]) by age, sex, and location. We used final prevalence estimates and disability weights to estimate years lived with disability and disability-adjusted life-years (DALYs) for major depressive disorder and anxiety disorders. Findings We identified 5683 unique data sources, of which 48 met inclusion criteria (46 studies met criteria for major depressive disorder and 27 for anxiety disorders). Two COVID-19 impact indicators, specifically daily SARS-CoV-2 infection rates and reductions in human mobility, were associated with increased prevalence of major depressive disorder (regression coefficient [ B ] 0·9 [95% uncertainty interval 0·1 to 1·8; p=0·029] for human mobility, 18·1 [7·9 to 28·3; p=0·0005] for daily SARS-CoV-2 infection) and anxiety disorders (0·9 [0·1 to 1·7; p=0·022] and 13·8 [10·7 to 17·0; p<0·0001]. Females were affected more by the pandemic than males ( B 0·1 [0·1 to 0·2; p=0·0001] for major depressive disorder, 0·1 [0·1 to 0·2; p=0·0001] for anxiety disorders) and younger age groups were more affected than older age groups (−0·007 [–0·009 to −0·006; p=0·0001] for major depressive disorder, −0·003 [–0·005 to −0·002; p=0·0001] for anxiety disorders). We estimated that the locations hit hardest by the pandemic in 2020, as measured with decreased human mobility and daily SARS-CoV-2 infection rate, had the greatest increases in prevalence of major depressive disorder and anxiety disorders. We estimated an additional 53·2 million (44·8 to 62·9) cases of major depressive disorder globally (an increase of 27·6% [25·1 to 30·3]) due to the COVID-19 pandemic, such that the total prevalence was 3152·9 cases (2722·5 to 3654·5) per 100 000 population. We also estimated an additional 76·2 million (64·3 to 90·6) cases of anxiety disorders globally (an increase of 25·6% [23·2 to 28·0]), such that the total prevalence was 4802·4 cases (4108·2 to 5588·6) per 100 000 population. Altogether, major depressive disorder caused 49·4 million (33·6 to 68·7) DALYs and anxiety disorders caused 44·5 million (30·2 to 62·5) DALYs globally in 2020. Interpretation This pandemic has created an increased urgency to strengthen mental health systems in most countries. Mitigation strategies could incorporate ways to promote mental wellbeing and target determinants of poor mental health and interventions to treat those with a mental disorder. Taking no action to address the burden of major depressive disorder and anxiety disorders should not be an option. Funding Queensland Health, National Health and Medical Research Council, and the Bill and Melinda Gates Foundation.

0 comments Cited 1301 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.

Amit Zeisel, Ana Muñoz-Manchado, Simone Codeluppi … (2015)

The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity. Copyright © 2015, American Association for the Advancement of Science.

0 comments Cited 705 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

R C Kessler, K McGonagle, S. Zhao … (1994)

This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.

0 comments Cited 657 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Mathias V. Schmidt:

ORCID: https://orcid.org/0000-0002-3788-2268

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Electronic, pub): 30 May 2023

Publication date (Print, pub): 6 June 2023

Publication date PMC-release: 30 May 2023

Volume: 120

Issue: 23

Electronic Location Identifier: e2300722120

Affiliations

[1] ^aResearch Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry , 80807 Munich, Germany

[2] ^bInternational Max Planck Research School for Translational Psychiatry , 80807 Munich, Germany

[3] ^cCore Unit Neuroimaging, Max Planck Institute of Psychiatry , 80807 Munich, Germany

[4] ^dResearch Group Molecular Neurogenetics, Max Planck Institute of Psychiatry , 80807 Munich, Germany

[5] ^eDepartment of Neuroscience, Karolinska Institute , Solna 171 77, Sweden

Author notes

¹To whom correspondence may be addressed. Email: mschmidt@ 123456psych.mpg.de .

Edited by Donald Pfaff, Rockefeller University, New York, NY; received January 16, 2023; accepted March 27, 2023

Author information

Lotte van Doeselaar https://orcid.org/0000-0003-1840-0574

Tibor Stark https://orcid.org/0000-0001-8118-9914

Joeri Bordes https://orcid.org/0000-0003-2909-2976

Jan M. Deussing https://orcid.org/0000-0002-9329-5252

Mathias V. Schmidt https://orcid.org/0000-0002-3788-2268

Article

Publisher ID: 202300722

DOI: 10.1073/pnas.2300722120

PMC ID: 10266018

PubMed ID: 37252963

SO-VID: edcf22a0-bd22-4210-933c-af9bfc5639f8

License:

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

History

Date received : 16 January 2023

Date accepted : 27 March 2023

Page count

Pages: 11, Words: 7152

Funding

Funded by: Deutsche Forschungsgemeinschaft (DFG), FundRef 501100001659;

Award ID: SCHM2360/3-1

Award Recipient : Mathias V Schmidt

Funded by: Bundesministerium für Bildung und Forschung (BMBF), FundRef 501100002347;

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

Read this article at

Significance

Abstract

Related collections

Pneumonia, sex, and the environment

Most cited references 89

Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic

Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.

Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 91

Cited by 2

Most referenced authors 1,422