Grape-derived polyphenols produce antidepressant effects via VGF- and BDNF-dependent mechanisms

Recent studies suggest that bioactive dietary polyphenol preparation (BDPP) and individual polyphenolic compounds ameliorate stress-induced depression-like behaviors, but the underlying molecular mechanisms are incompletely understood. VGF (non-acronymic) in the dorsal hippocampus (dHc) has been shown to play a role in depression-like behaviors and antidepressant efficacy, and the VGF-derived peptide TLQP-62 (named by the N-terminal 4 amino acids and length) infused into dHc has been shown to have antidepressant efficacy that is BDNF-TrkB dependent. Here, we investigated whether BDPP influences VGF expression in the dHc, and whether dHc VGF is required for BDPP antidepressant efficacy. We found that BDPP produced antidepressant-like effects in naive mice and reversed the depression-like behaviors induced by chronic variable stress. In addition, we found that BDPP had no detectable antidepressant efficacy in floxed mice with prior knockdown in the dHc of either VGF or BDNF, achieved by adeno-associated virus-Cre infusion. Our data indicate that dHc VGF and BDNF expression are required for the antidepressant actions of BDPP, and therefore suggest that a VGF(TLQP-62)-BDNF-TrkB autoregulatory feedback loop could play a role in the regulation of BDPP antidepressant efficacy, much as it has been suggested to function in the antidepressant efficacies of ketamine and TLQP-62.