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

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.

SUBMITTER: van Doeselaar L

PROVIDER: S-EPMC10266018 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

van Doeselaar Lotte L Stark Tibor T Mitra Shiladitya S Yang Huanqing H Bordes Joeri J Stolwijk Linda L Engelhardt Clara C Kovarova Veronika V Narayan Sowmya S Brix Lea M LM Springer Margherita M Deussing Jan M JM Lopez Juan Pablo JP Czisch Michael M Schmidt Mathias V MV

Proceedings of the National Academy of Sciences of the United States of America 20230530 23

Mental health disorders often arise as a combination of environmental and genetic factors. The <i>FKBP5</i> 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 b ...[more]

PMID: 37252963

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Project description:Early life stress (ELS) has often been described as a risk factor for developing psychiatric disease. However, moderate exposure to ELS can also lead to stress inoculation and consequently adaptive changes on brain and behavior. Moreover, the FKBP5 gene, encoding the FKBP51 co-chaperone, has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. However, the underlying mechanisms behind the interaction of FKBP51 and moderate ELS exposure are still not completely understood and particularly data in the female sex are scarce. In this study, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of moderate ELS was investigated in both sexes, by using the Fkbp5Nex conditional knockout line. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in in Fkbp5Nexx wild-type mice. Interactive effects of FKBP51 in glutamatergic forebrain neurons and moderate ELS exposure in female mice were also reflected on brain volume of different cortical regions, the subiculum and white matter structures. Furthermore, interactive effects were observed for structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of these interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the moderate ELS exposure. Taken together, this study shows that FKBP51 in glutamatergic forebrain neurons mediates adaptive effects of moderate ELS exposure on emotional regulation, cognitive behavior and neuronal structure and function. Moreover, it proposes TCF4 as an underlying target that drives the FKBP51-mediated effects of moderate ELS on brain and behavior.

Dataset Information

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

Publications

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

Similar Datasets

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