Mechanisms by which sevoflurane affects cognitive function in aged marmosets and mice: up-regulation of FKBP5
Lei Zhang1,2, Jiao Zhu1, Zhengjie Miao1
1Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Inhalation anesthetics may trigger the hypothalamic-pituitary-adrenal axis. FK-506 binding protein (FKBP5) is a critical regulator of the hypothalamic-pituitary-adrenal axis and has been implicated in postoperative cognitive dysfunction. However, how inhalation anesthetics affect the expression and function of FKBP5 in the brain is unclear. We employed single-nucleus RNA sequencing to delineate the hippocampal transcriptomic profiles of the brains of aged marmosets and mice after sevoflurane anesthesia. The results of single-nucleus RNA sequencing revealed that long-term exposure (6 hours) to sevoflurane significantly increased FKBP5 expression in the hippocampus of aged marmosets and mice, especially in microglia. Western blot assay also verified the above results. The Barnes maze test showed that, compared with heterozygous control mice, microglia-specific FKBP5 conditional knockout mice exhibited improved neurocognitive function after sevoflurane/surgery. Transcriptome sequencing analysis was performed on the brains of microglia-specific FKBP5 conditional knockout mice and heterozygous mice after sevoflurane/surgery and further revealed that FKBP5 was related mainly to inflammatory signaling pathways. Therefore, these findings indicate that long-term exposure to sevoflurane increases FKBP5 expression in the hippocampus of aged marmosets and mice, which thereby affects inflammatory signaling pathways and leads to postoperative cognitive dysfunction.
Insights
Long-term sevoflurane anesthesia increases FKBP5 expression in the hippocampus, particularly in microglia. This elevates inflammatory signaling, contributing to postoperative cognitive dysfunction in aged animals.
Area of Science:
- Neuroscience
- Anesthesiology
- Molecular Biology
Background:
- Inhalation anesthetics can activate the hypothalamic-pituitary-adrenal axis.
- FK-506 binding protein (FKBP5) regulates this axis and is linked to postoperative cognitive dysfunction.
- The impact of anesthetics on brain FKBP5 expression and function remains unclear.
Purpose of the Study:
- To investigate how sevoflurane anesthesia affects FKBP5 expression and function in the aged brain.
- To determine the role of FKBP5 in sevoflurane-induced neurocognitive deficits.
Main Methods:
- Single-nucleus RNA sequencing of aged marmoset and mouse hippocampi post-sevoflurane anesthesia.
- Western blot analysis to confirm FKBP5 expression changes.
- Behavioral testing (Barnes maze) in microglia-specific FKBP5 conditional knockout mice.
- Transcriptome sequencing of knockout and control mice.
Main Results:
- Sevoflurane anesthesia significantly increased hippocampal FKBP5 expression, especially in microglia, in aged marmosets and mice.
- Microglia-specific FKBP5 knockout mice showed improved neurocognitive function after sevoflurane/surgery.
- FKBP5 was primarily associated with inflammatory signaling pathways.
Conclusions:
- Long-term sevoflurane exposure upregulates hippocampal FKBP5 in aged animals.
- Increased FKBP5 expression in microglia contributes to postoperative cognitive dysfunction via inflammatory pathways.
