FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus
Abstract Background Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inf...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02517-8 |
| _version_ | 1818237130057449472 |
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| author | Yu-Ling Gan Chen-Yu Wang Rong-Heng He Pei-Chien Hsu Hsin-Hsien Yeh Tsung-Han Hsieh Hui-Ching Lin Ming-Yen Cheng Chung-Jiuan Jeng Ming-Chyi Huang Yi-Hsuan Lee |
| author_facet | Yu-Ling Gan Chen-Yu Wang Rong-Heng He Pei-Chien Hsu Hsin-Hsien Yeh Tsung-Han Hsieh Hui-Ching Lin Ming-Yen Cheng Chung-Jiuan Jeng Ming-Chyi Huang Yi-Hsuan Lee |
| author_sort | Yu-Ling Gan |
| collection | DOAJ |
| description | Abstract Background Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. Methods Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. Results LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. Conclusions These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety. |
| first_indexed | 2024-12-12T12:20:52Z |
| format | Article |
| id | doaj.art-c879189580ec4a1f8000b3c9bf60c8c3 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-12T12:20:52Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-c879189580ec4a1f8000b3c9bf60c8c32022-12-22T00:24:40ZengBMCJournal of Neuroinflammation1742-20942022-06-0119112110.1186/s12974-022-02517-8FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampusYu-Ling Gan0Chen-Yu Wang1Rong-Heng He2Pei-Chien Hsu3Hsin-Hsien Yeh4Tsung-Han Hsieh5Hui-Ching Lin6Ming-Yen Cheng7Chung-Jiuan Jeng8Ming-Chyi Huang9Yi-Hsuan Lee10Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityBrain Research Center, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityDepartment of Mathematics, Hong Kong Baptist UniversityBrain Research Center, National Yang Ming Chiao Tung UniversityDepartment of Psychiatry, Taipei City Psychiatric Center, Taipei City HospitalDepartment and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung UniversityAbstract Background Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. Methods Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. Results LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. Conclusions These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.https://doi.org/10.1186/s12974-022-02517-8FK506-binding protein 51 (FKBP51)InflammationAnxietyResilienceGlucocorticoid receptorGlutamic acid decarboxylase 65 (GAD65) |
| spellingShingle | Yu-Ling Gan Chen-Yu Wang Rong-Heng He Pei-Chien Hsu Hsin-Hsien Yeh Tsung-Han Hsieh Hui-Ching Lin Ming-Yen Cheng Chung-Jiuan Jeng Ming-Chyi Huang Yi-Hsuan Lee FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus Journal of Neuroinflammation FK506-binding protein 51 (FKBP51) Inflammation Anxiety Resilience Glucocorticoid receptor Glutamic acid decarboxylase 65 (GAD65) |
| title | FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus |
| title_full | FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus |
| title_fullStr | FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus |
| title_full_unstemmed | FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus |
| title_short | FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus |
| title_sort | fkbp51 mediates resilience to inflammation induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus |
| topic | FK506-binding protein 51 (FKBP51) Inflammation Anxiety Resilience Glucocorticoid receptor Glutamic acid decarboxylase 65 (GAD65) |
| url | https://doi.org/10.1186/s12974-022-02517-8 |
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