ARHGAP39 plays an essential role in anxiety-like behavior and stress response

Anxiety is a common mental health disorder marked by heightened stress responses and impaired emotional regulation. While the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis play key roles in regulating anxiety, the molecular mechanisms remain incompletely understood. In this study, we identified a strong link between ARHGAP39 function and anxiety using brain-specific Arhgap39 conditional knockout (cKO) mice. ARHGAP39 is a brain-enriched Rho GTPase-activating protein implicated in neurodevelopment and synaptic regulation. Arhgap39 cKO mice exhibited ectopic progenitor cells in the hilus of the hippocampus during early postnatal development, along with impaired adult neurogenesis in dentate gyrus (DG). Behaviorally, adult cKO mice demonstrated pronounced anxiety-like phenotypes without cognitive impairments, whereas aged cKO mice exhibited persistent anxiety accompanied by learning and memory deficits. Molecular profiling revealed that cKO mice exhibited significantly elevated RNA expression levels of glutamatergic and glucocorticoid receptor-related genes in the hippocampus. In addition, cKO mice exhibited more stress-activated neurons in the DG. Mechanistically, Arhgap39 deficiency disrupted Rho GTPase–related actin pathways, leading to elevated Cofilin-1 and Arp3 expression and reduced PSD-95 levels, suggesting disruption of synaptic organization. Finally, hippocampal overexpression of Arhgap39 in C57BL/6 mice did not affect baseline behavior but alleviated chronic stress-induced anxiety in light-dark box test. In conclusion, our findings demonstrate that ARHGAP39 plays a critical role in modulating anxiety, hippocampal neurogenesis, and synaptic stability, highlighting it as a promising target for developing anxiolytic therapies.