FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice
Abstract Early life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57952-x |
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| author | Lotte van Doeselaar Alexandra Abromeit Tibor Stark Danusa Menegaz Markus Ballmann Shiladitya Mitra Huanqing Yang Ghalia Rehawi Rosa-Eva Huettl Joeri Bordes Sowmya Narayan Daniela Harbich Jan M. Deussing Gerhard Rammes Michael Czisch Janine Knauer-Arloth Matthias Eder Juan Pablo Lopez Mathias V. Schmidt |
| author_facet | Lotte van Doeselaar Alexandra Abromeit Tibor Stark Danusa Menegaz Markus Ballmann Shiladitya Mitra Huanqing Yang Ghalia Rehawi Rosa-Eva Huettl Joeri Bordes Sowmya Narayan Daniela Harbich Jan M. Deussing Gerhard Rammes Michael Czisch Janine Knauer-Arloth Matthias Eder Juan Pablo Lopez Mathias V. Schmidt |
| author_sort | Lotte van Doeselaar |
| collection | DOAJ |
| description | Abstract Early life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of ELS was investigated in both sexes. In female wild-type Fkbp5 lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in Fkbp5 Nex mice. These interactive FKBP51 x ELS effects in female mice were also reflected in reduced brain region volumes, and on structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. In contrast, the behavioral, structural and functional effects in male ELS mice were less pronounced and independent of FKBP51. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of the female interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the ELS exposure. This study demonstrates a sex-specific role for FKBP51 in mediating the adaptive effects of ELS on emotional regulation, cognition, and neuronal function, implicating TCF4 as a downstream effector. |
| format | Article |
| id | doaj-art-8e7100adba81469fbeda2e3233b0ebda |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8e7100adba81469fbeda2e3233b0ebda2025-08-20T02:56:20ZengNature PortfolioNature Communications2041-17232025-03-0116111610.1038/s41467-025-57952-xFKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female miceLotte van Doeselaar0Alexandra Abromeit1Tibor Stark2Danusa Menegaz3Markus Ballmann4Shiladitya Mitra5Huanqing Yang6Ghalia Rehawi7Rosa-Eva Huettl8Joeri Bordes9Sowmya Narayan10Daniela Harbich11Jan M. Deussing12Gerhard Rammes13Michael Czisch14Janine Knauer-Arloth15Matthias Eder16Juan Pablo Lopez17Mathias V. Schmidt18Research Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryCore Unit Neuroimaging, Max Planck Institute of PsychiatryCore Unit Electrophysiology, Max Planck Institute of PsychiatryKlinik für Anaesthesiologie und Intensivmedizin der Technischen Universität München, Klinikum Rechts der IsarResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryDepartment Genes & Environment, Max Planck Institute of PsychiatryCore Unit Virus Production, Max Planck Institute of PsychiatryResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryResearch Group Molecular Genetics, Max Planck Institute of PsychiatryKlinik für Anaesthesiologie und Intensivmedizin der Technischen Universität München, Klinikum Rechts der IsarCore Unit Neuroimaging, Max Planck Institute of PsychiatryDepartment Genes & Environment, Max Planck Institute of PsychiatryCore Unit Electrophysiology, Max Planck Institute of PsychiatryDepartment of Neuroscience, Karolinska InstituteResearch Group Neurobiology of Stress Resilience, Max Planck Institute of PsychiatryAbstract Early life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of ELS was investigated in both sexes. In female wild-type Fkbp5 lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in Fkbp5 Nex mice. These interactive FKBP51 x ELS effects in female mice were also reflected in reduced brain region volumes, and on structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. In contrast, the behavioral, structural and functional effects in male ELS mice were less pronounced and independent of FKBP51. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of the female interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the ELS exposure. This study demonstrates a sex-specific role for FKBP51 in mediating the adaptive effects of ELS on emotional regulation, cognition, and neuronal function, implicating TCF4 as a downstream effector.https://doi.org/10.1038/s41467-025-57952-x |
| spellingShingle | Lotte van Doeselaar Alexandra Abromeit Tibor Stark Danusa Menegaz Markus Ballmann Shiladitya Mitra Huanqing Yang Ghalia Rehawi Rosa-Eva Huettl Joeri Bordes Sowmya Narayan Daniela Harbich Jan M. Deussing Gerhard Rammes Michael Czisch Janine Knauer-Arloth Matthias Eder Juan Pablo Lopez Mathias V. Schmidt FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice Nature Communications |
| title | FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice |
| title_full | FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice |
| title_fullStr | FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice |
| title_full_unstemmed | FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice |
| title_short | FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice |
| title_sort | fkbp51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice |
| url | https://doi.org/10.1038/s41467-025-57952-x |
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