Acute vitamin B12 supplementation evokes antidepressant response and alters Ntrk-2

Depression is the leading cause of disability worldwide. Although most research into risk factors focuses on stress, dietary factors also have a strong link with depression. For instance, chronic vitamin B12-supplementation may reduce depression risk and helps to reverse the prodepressive effects of early life stress in animal models. However, it is still unclear whether a single acute dose of vitamin B12 is sufficient to induce antidepressant effects on molecular or behavioral levels. Based on pharmacological work and CRISPR-dCas9 epigenome editing in Neuro2A-cells we provide in vitro evidence for a link between vitamin B12, gene expression and DNA methylation of the antidepressant-associated gene Ntrk-2, which codes for the BDNF-receptor TRKB. Using stress-induction protocols in C57Bl/6 J mice combined with behavioral testing and subsequent molecular tissue analysis, we establish in vivo evidence for antidepressant effects of vitamin B12. Acute supplementation with vitamin B12, but not folic acid, selectively altered DNA methylation and gene expression of Ntrk-2 in vitro, albeit DNA methylation and Ntrk-2 gene expression do not correlate in vivo. Importantly, one acute vitamin B12 injection improved multiple behavioral measures in tests for antidepressant action and at the same time reversed the effects of chronic and acute stress on Ntrk-2 levels in vivo, however causality has not been proven at this stage. Taken together, acute vitamin B12 supplementation can reverse stress effects on Ntrk-2 gene expression and improve behaviors that are associated with depression-like behavior in mice. Our findings encourage further investigation of vitamin B12-supplementation as a novel model for antidepressant action.