PDGF-BB-Dependent Neurogenesis Buffers Depressive-Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus

Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains unclear. Here, it is shown that inhibition of medial septum (MS)-dentate gyrus (DG) circuit reverses the chronic social defeat stress (CSDS)-induced depression-like behavior. Further analysis exhibits that inhibition of gamma-aminobutyric acidergic neurons in MS projecting to the DG (MSGABA+-DG) increases the expression of platelet-derived growth factor-BB (PDGF-BB) in somatostatin (SOM) positive interneurons of DG, which contributes to the antidepressant-like effects. Overexpression of the PDGF-BB or exogenous administration of PDGF-BB in DG rescues the effect of chronic stress on the inhibition of neural stem cells (NSCs) proliferation and dendritic growth of adult-born hippocampal neurons, as well as on depressive-like behaviors. Conversely, knockdown of PDGF-BB facilitates CSDS-induced deficit of hippocampal neurogenesis and promotes the susceptibility to chronic stress in mice. Finally, conditional knockdown platelet-derived growth factor receptor beta (PDGFR beta) in NSCs blocks an increase in NSCs proliferation and the antidepressant effects of PDGF-BB. These results delineate a previously unidentified PDGF-BB/PDGFR beta signaling in regulating depressive-like behaviors and identify a novel mechanism by which the MSGABA+-DG pathway regulates the expression of PDGF-BB in SOM-positive interneurons.

Automated summary

This study reveals that inhibiting the medial septum-dentate gyrus circuit can reverse depression-like behavior induced by chronic social defeat stress. Further analysis shows that inhibiting gamma-aminobutyric acidergic neurons in the medial septum projecting to the dentate gyrus increases the expression of platelet-derived growth factor-BB in somatostatin positive interneurons of the dentate gyrus, contributing to the antidepressant-like effects. Overexpression or exogenous administration of platelet-derived growth factor-BB in the dentate gyrus rescues the inhibitory effects of chronic stress on neural stem cells proliferation, dendritic growth of adult-born hippocampal neurons, and depressive-like behaviors.