A female-specific role for Slit1 in prenatal stress-induced depression vulnerability

Women experience nearly twice the prevalence of depression compared to men and frequently present with comorbid anxiety, with this divergence emerging during adolescence. However, the molecular mechanisms underlying female-specific depression vulnerability remain poorly understood. Here, we found that prenatal stress (PS) induced depressive-like behaviors and selectively downregulated Slit Guidance Ligand 1 (Slit1) expression in the hippocampal dentate gyrus (DG) of female adolescent offspring rats. Furthermore, viral knockdown of Slit1 in the DG induced anxiety- and depressive-like behavioral phenotypes specifically in female rats. In females, Slit1 deficiency reduced the mean fluorescence intensity of the neural stem cell and immature neuron markers Sox2 and DCX in the DG, decreased postsynaptic Homer1, PSD95, and GluA1 expression without affecting Synaptophysin, and diminished the amplitude of sEPSCs. Significantly, the downstream Slit1 effector SLIT-ROBO Rho GTPase-activating protein 2 (Srgap2) was downregulated specifically in Slit1-deficient females. Together, these results suggest that Slit1 disruption selectively affects DG neuroplasticity in females and may contribute to their heightened vulnerability to PS-related depressive-like behaviors, although further mechanistic studies are required to confirm the causal role of Slit1 in these effects.