Prenatal stress selectively enhances locomotor hyperactivity in male mice with embryonic loss of Fgfr2.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental psychiatric disorder associated with a complex interplay of genetic and environmental risk factors. In a previous study, we found embryonic dorsal forebrain loss in male 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 performed a follow-up study by pairing 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, dopamine transporter (DAT) levels, and pilot parvalbumin-positive (PV+) cell densities. Offspring of prenatally stressed, Fgfr2 cKO male mice showed increased locomotion (80% higher compared to non-stressed, Fgfr2 cKO animals). However, prenatal stress had no significant effects on impulsivity, working memory, or sociability in Fgfr2 cKO male mice. Neurobiologically, prenatal stress did not significantly affect DAT levels, and DAT protein levels did not correlate with behavior, suggesting DAT dysregulation is not the mechanism of increased locomotion in this model. Taken together, our findings implicate prenatal stress as a potential contributor to some gene-environment interactions for ADHD risk, supporting its use in translational animal models of childhood psychiatric disorders.