FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number152
JournalJournal of Neuroinflammation
Volume19
Issue number1
DOIs
Publication statusPublished - 15 Jun 2022

Scopus Subject Areas

  • Neurology
  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Immunology

User-Defined Keywords

  • Anxiety
  • FK506-binding protein 51 (FKBP51)
  • GABA
  • Glucocorticoid receptor
  • Glutamic acid decarboxylase 65 (GAD65)
  • Inflammation
  • Resilience
  • Ventral hippocampus

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