Vitamin D binding protein in ventral CA3 of the hippocampus drives stress-induced depression

The ventral hippocampus plays a crucial role in regulating emotional and motivated behaviors. However, the molecular mechanisms underlying its dysfunction in major depressive disorder (MDD) remain poorly understood. Here, we identified elevated expression of vitamin D binding protein (VDBP) in the hippocampi of chronic unpredictable mild stress (CUMS)-susceptible mice, which correlated with the severity of depression-like behaviors. Notably, VDBP up-regulation was specifically in ventral CA3 excitatory (vCA3^CaMKIIα) neurons. CA3^CaMKIIα VDBP overexpression led to inhibited neuronal activity, synaptic and dendritic impairments, and, ultimately, depression-like behaviors. Conversely, vCA3^CaMKIIα-specific VDBP knockdown enhanced resilience to chronic stress. Mechanistically, VDBP directly interacted with PIK3R3 to inhibit the PI3K-Akt-mTOR pathway in a cell-autonomous manner, leading to excessive autophagy and subsequent neuronal dysfunction. Chemogenetic activation, intervention using the Akt-specific activator SC79, and site-specific mutation disrupting the VDBP-PIK3R3 interaction ameliorated vCA3^CaMKIIα VDBP-induced depression-like phenotypes. Collectively, these findings underscore the critical involvement of vCA3^CaMKIIα neuron-derived VDBP in stress-induced depressive pathology and highlight its potential as a therapeutic target for MDD.