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

ABSTRACT: The ventral hippocampus is a critical region in regulating emotional and motivated behaviors. However, the molecular mechanism underlying its dysfunction in the pathogenesis of major depressive disorder (MDD) is still elusive. Here, we found increased expression of vitamin D binding protein (VDBP) in the hippocampi of MDD patients and chronic unpredictable mild stress (CUMS) susceptible mice, which was correlated with the severity of depression-like behaviors in mice. Specifically, hippocampal VDBP upregulation was restricted to the glutamatergic neurons in the ventral Cornu Ammonis 3 (vCA3) region of CUMS-susceptible mice. Recombinant adeno-associated virus (rAAV)-mediated VDBP overexpression in vCA3 glutamatergic neurons induced depression-like behaviors in mice, accompanied by impaired neuronal structure and activities, whereas VDBP-targeted knockdown increased the resilience to CUMS. Mechanistically, VDBP directly interacted with phosphoinositide 3-kinase (PI3K) regulatory subunit 3 (PIK3R3) to inhibit the PI3K-protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) signaling cascade in a cell-autonomous manner, leading to overactivated autophagy and neuronal dysfunction. Consequently, depression-like behaviors were induced by chemogenetic inhibition of vCA3 glutamatergic neurons. Pharmacological intervention with Akt-specific activator SC79 or chemogenetic activation rescued depression-like phenotypes induced by VDBP overexpression in vCA3 glutamatergic neurons. Overall, our study demonstrates the critical role of vCA3 neuron-derived VDBP in stress-induced depression, highlighting its potential as a diagnostic biomarker and therapeutic target for MDD.

ORGANISM(S): Mus musculus

PROVIDER: GSE312956 | GEO | 2026/09/02

REPOSITORIES: GEO