FKBP51 通过调节小鼠海马谷氨酸脱羧酶 65 的表达介导对炎症诱导的焦虑的抵抗力。

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

机构信息

Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, 155 Sec. 2, Linong Street, Taipei, 112, Taiwan.

Brain Research Center, National Yang Ming Chiao Tung University, 155 Sec. 2, Linong Street, Taipei, 112, Taiwan.

出版信息

J Neuroinflammation. 2022 Jun 15;19(1):152. doi: 10.1186/s12974-022-02517-8.

DOI:10.1186/s12974-022-02517-8

PMID:35705957

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9198626/

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 [F]-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.

摘要

背景

炎症是精神障碍的潜在风险因素。FKBP5 是编码 FK506 结合蛋白 51（FKBP51）的基因，FKBP51 是糖皮质激素受体（GR）的负共伴侣，是一种应激诱导基因，与精神疾病有关。然而，FKBP51 在炎症应激相关精神障碍中的作用尚不清楚。

方法

使用 Fkbp5 基因敲除（Fkbp5-KO）小鼠通过单次腹腔注射脂多糖（LPS）来研究炎症应激。评估焦虑样行为、神经影像学、免疫荧光染色、免疫组织化学、炎症和神经递质相关介质的蛋白和 mRNA 表达分析。还应用地塞米松饮水模型来研究 Fkbp5-KO 在糖皮质激素诱导应激中的作用。

结果

LPS 给药诱导肝脏和海马中 FKBP51 升高，并伴有短暂的疾病。值得注意的是，LPS 注射后 7 天（LPS-D7），Fkbp5-KO 而不是野生型（WT）小鼠表现出焦虑样行为。LPS 刺激迅速增加外周和中枢免疫反应以及海马小胶质细胞激活，随后在 LPS-D7 时 GR 上调延迟，这些效应在 Fkbp5-KO 小鼠中减弱。全脑 [F]-FEPPA 神经影像学，以转位蛋白（TSPO）为靶点来指示神经炎症，显示 Fkbp5-KO 减少了 LPS 诱导的各种脑区包括海马中的神经炎症。有趣的是，LPS 在 LPS-D7 时 WT 但不是 Fkbp5-KO 小鼠的海马中升高谷氨酸脱羧酶 65（GAD65），这是一种膜相关 GABA 合成酶。在 LPS-D7 时，FKBP51 依赖性 GAD65 上调发生在腹侧海马 CA1 区，伴随着 c-Fos 指示的神经元活动减少，而在背侧 CA1 区，GAD65 和神经元活动均以 FKBP51 非依赖性方式减少。还检查了 GC 诱导的焦虑，其在 Fkbp5-KO 中减弱，而海马 GAD65 表达不受影响。