Prenatal stress interacts with embryonic loss of Fgfr2 to increase locomotor hyperactivity in mice

Attention-deficit/hyperactivity disorder (ADHD) is a developmental psychiatric disorder associated with a complex interplay of genetic and environmental risk factors. We have shown embryonic dorsal forebrain loss in mice of fibroblast growth factor receptor 2 ( Fgfr2 ), which has a critical role in normal brain development, results in ADHD-relevant phenotypes: increased locomotion and sociability, and impaired working memory postnatally. How such genetic vulnerabilities interact with environmental exposures to translationally model human ADHD risk remains unclear. Here, we pair the embryonic hGFAP-cre Fgfr2 conditional knockout ( Fgfr2 cKO) mouse model with prenatal repetitive restraint stress, modeling an environmental factor associated with ADHD risk, to assess adult offspring behaviors and dopamine transporter (DAT) levels. Offspring of prenatally stressed, Fgfr2 cKO mice show increased locomotion (80% compared to non-stressed, Fgfr2 cKO animals). Prenatal stress led to a trend increase in impulsivity and trend decrease in working memory but did not affect sociability. There were no interactions with Fgfr2 cKO observed in these behaviors. Neurobiologically, prenatal stress led to a trend decrease in medial frontal cortex DAT, but these changes did not correlate with behavior. Taken together, our findings implicate prenatal stress as a potential contributor to gene-environment interactions for ADHD risk, supporting its use in translational animal models of childhood psychiatric disorders.