Boehringer Ingelheim Pharma GmbH & Co KG, CNSDR, Ingelheim, Germany.
Institute of Psychology & Education, Clinical & Biological Psychology, Ulm University, Ulm, Germany.
Eur J Neurosci. 2021 Jan;53(2):402-415. doi: 10.1111/ejn.14999. Epub 2020 Oct 27.
The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism-associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5-humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5-related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.
大脑是整合内部和外部条件的中枢，也是应激反应的调节者。糖皮质激素是这种反应的重要传递者。糖皮质激素信号转导的异常是精神疾病患者的常见症状。FKBP5 基因编码一种伴侣蛋白，它能抑制糖皮质激素信号转导，从而有助于应激的调节。在儿童创伤的背景下，与对照组相比，精神病患者的 FKBP5 表达出现差异。据报道，FKBP5 表达水平的这些变化与人类单核苷酸多态性（SNP）rs1360780 携带者的应激反应差异有关。了解 FKBP5 多态性与中枢神经系统糖皮质激素反应相关的机制将有助于更好地理解应激调节或相关的病理。为了研究这些机制，生成了两种新型的人源化小鼠品系。这些品系携带 rs1360780 的风险（A/T）等位基因或弹性（C/G）等位基因。分析了来自中枢神经系统（星形胶质细胞、小胶质细胞和神经元）的原代细胞的 FKBP5 基础表达水平及其对糖皮质激素的反应性。发现这些细胞类型的 FKBP5 表达存在差异，并且与细胞糖皮质激素反应性呈负相关。星形胶质细胞表现出最强的转录反应，其次是小胶质细胞和神经元。此外，风险等位基因（A/T）与 FKBP5 诱导的增加有关，而弹性等位基因则不然。由于单个内含子 SNP，新型 FKBP5 人源化小鼠表现出不同的糖皮质激素反应性。大脑中糖皮质激素的应激信号易感性与 FKBP5 表达水平相关。星形胶质细胞对糖皮质激素的强烈反应表明星形胶质细胞在应激反应中起着重要作用，并且在 FKBP5 相关的糖皮质激素信号转导差异中起着重要作用。新型人源化小鼠品系将允许进一步研究 FKBP5 SNPs 在应激病理的风险和弹性中的作用。
