FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells - First insights from novel humanized mice.

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.