Abstract
The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviorally relevant context, we generated humanized mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioral and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition and sex. In humanized females carrying the CG-but not the AT-allele, ELA led to altered HPA-axis functioning, exploratory behavior and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.
Competing Interest Statement
Isabella Harris and Iris-Tatiana Kolassa declare no conflict of interest. Kelly Ann Allers, Andrea Blasius, Bastian Hengerer, Eliza Koros, Verena Nold, Tatiana Peleh and Michelle Portenhauser are employees at Boehringer Ingelheim Pharma GmbH & Co KG. Michal Slezak and Dolores Del Prete were employees at BioMedX during preparation of data used in this publication. The funding for this study was provided by Boehringer Ingelheim Pharma GmbH & Co KG to provide a doctorate thesis project to Verena Nold. The company had no further influence on this work.