Vitamin D3/vitamin D receptor signaling mitigates symptoms of post-stroke depression in mice by upregulating hippocampal BDNF expression

Elucidation of the pathogenic mechanisms underlying post-stroke depression (PSD) could aid in the development of effective treatments. The present study explored whether Vitamin D3 (VitD3) can function as an antidepressant in PSD model mice and whether the effect is mediated by upregulation of brain-derived neurotrophic factor (BDNF). Mice were subjected to middle cerebral artery occlusion (MCAO) combined with chronic unpredicted mild stress (CUMS) to established the PSD model. For the mice in each group, Longa and Berderson behavioral tests were performed to evaluate motor function, sucrose preference and forced swimming tests were conducted to assess the cardinal depression-like behaviors anhedonia and helplessness, and western blot and immunohistochemistry were conducted to measure the levels of vitamin D receptor (VDR) and BDNF expression levels in mouse hippocampus. Compared to MCAO alone, subsequent CUMS aggravated motor dysfunction and depression-like behaviors, whereas injection of calcitriol (VitD3) enhanced expression levels of VDR and BDNF in the hippocampus as well as ameliorated both motor dysfunction and depression-like behaviors of PSD model mice, with optimal efficacy at 25 μg/kg. Injection of a BDNF-binding protein (TrkB-IgG) almost completely reversed the antidepressant and neuroprotective effects of VitD3, strongly suggesting that VitD3 improved motor dysfunction and depression-like behaviors in PSD model mice by promoting hippocampal BDNF signaling. Modulation of hippocampal BDNF by VitD3 treatment could be an effective strategy for prevention and treatment of PSD.