FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice

Early life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of ELS was investigated in both sexes. In female wild-type Fkbp5^lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in Fkbp5^Nex mice. These interactive FKBP51 x ELS effects in female mice were also reflected in reduced brain region volumes, and on structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. In contrast, the behavioral, structural and functional effects in male ELS mice were less pronounced and independent of FKBP51. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of the female interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the ELS exposure. This study demonstrates a sex-specific role for FKBP51 in mediating the adaptive effects of ELS on emotional regulation, cognition, and neuronal function, implicating TCF4 as a downstream effector.