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

van Doeselaar, Lotte; Stark, Tibor; Mitra, Shiladitya; Yang, Huanqing; Bordes, Joeri; Stolwijk, Linda; Engelhardt, Clara; Kovarova, Veronika; Narayan, Sowmya; Brix, Lea M.; Springer, Margherita; Deussing, Jan M.; Lopez, Juan Pablo; Czisch, Michael; Schmidt, Mathias V.

doi:10.1073/pnas.2300722120

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

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van Doeselaar, Lotte
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons263007

Stark, Tibor
RG Neuronal Plasticity, Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262507

Mitra, Shiladitya
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons261972

Yang, Huanqing
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons261974

Bordes, Joeri
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons291645

Stolwijk, Linda
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons207257

Engelhardt, Clara
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons287957

Kovarova, Veronika
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262411

Narayan, Sowmya
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons261977

Brix, Lea M.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262511

Springer, Margherita
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80301

Deussing, Jan M.
RG Molecular Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222540

Lopez, Juan Pablo
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80295

Czisch, Michael
Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, Mathias V.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

van Doeselaar, L., Stark, T., Mitra, S., Yang, H., Bordes, J., Stolwijk, L., et al. (2023). Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120(23): e2300722120. doi:10.1073/pnas.2300722120.

Cite as: https://hdl.handle.net/21.11116/0000-000D-9497-1

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 uncov-ered 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 behav-ioral, 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 glu-tamatergic (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.