Fig. 5: Tcf4 overexpression leads to similar beneficial effects on behaviour as ELS exposure in Fkbp5^lox/lox mice.

To investigate whether TCF4 in glutamatergic neurons of the hippocampus is indeed the underlying molecular target regulating the beneficial effects of ELS exposure on behaviour, we overexpressed Tcf4 in these neurons by injecting an AVV Cre-dependent Tcf4 overexpression (OE) virus in Nex-Cre female mice of 6 months of age and compared them to female mice that were injected with an AVV GFP control virus (A). Interestingly, TCF4 OE indeed leads to (B) an anxiolytic phenotype on the elevated plus maze (EPM) test, like was observed upon ELS exposure in Fkbp5^lox/lox mice. Furthermore, data from the MWM showed that TCF4 OE mice had an improved memory of the platform location on the 3rd training day, which was a less strong but similar effect to as was observed for ELS-exposed female Fkbp5^lox/lox mice. n = 15 per group. Error bars represent mean + S.E.M. Panel B: Wilcoxon signed-rank test. Panel (C): repeated measures ANOVA. *p < 0.05; **p < 0,01; ***p < 0.001. Images of mouse head and MWM created in BioRender. Schmidt, M. (2025) https://BioRender.com/o64z476.