Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV

Promoter IV-driven expression of brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is implicated in the pathophysiology of major depression. We previously reported that mice lacking expression of BDNF through promoter IV (BDNF-KIV mice) exhibit a depression-like phenotype. Here, we examined whether the depression-like phenotype and decreased levels of BDNF because of promoter IV deficit could be rescued by enriched environment (EE) treatment, a potential antidepressant intervention. Three weeks of EE treatment rescued depression-like behavior of BDNF-KIV mice as assessed by the tail suspension test, open-field test and sucrose preference test. EE treatment also increased BDNF transcripts driven by multiple endogenous promoters and restored BDNF protein levels in the hippocampus (HIP) of BDNF-KIV mice. Further, we investigated adult hippocampal neurogenesis as a possible cellular mechanism underlying the depression-like behavior and its recovery in BDNF-KIV mice. We found that the number of surviving progenitors and their dendritic length in the dentate gyrus of the HIP were reduced in BDNF-KIV mice compared with the control wild-type mice. EE treatment restored the reduction in cell survival and dendritic length and increased cell proliferation in BDNF-KIV mice. In conclusion, this study demonstrated that EE rescued depression-like behavior, decreased BDNF levels and defective neurogenesis in the HIP caused by lack of promoter IV-driven BDNF expression. These results suggest that decreased BDNF levels because of one impaired promoter can be compensated by other BDNF promoters and that BDNF levels may be one of the key factors regulating depression and antidepressant effects through hippocampal neurogenesis.