The antidepressant-like effect elicited by vitamin D₃ is associated with BDNF/TrkB-related synaptic protein synthesis

Vitamin D₃ (cholecalciferol) has been shown to exert antidepressant-like responses, but the role BDNF/TrkB-related synaptic plasticity in this effect remains to be established. Thus, this study investigated the time-course antidepressant-like response of vitamin D₃ in female and male mice and the possible role of BDNF/TrkB signaling in this response. The repeated (7 and 21 days), but not acute (60 min), administration of vitamin D₃ (2.5 μg/kg, p.o.) exerted an antidepressant-like effect in female and male mice subjected to the tail suspension test, without altering the basal locomotor activity in the open-field test. Notably, vitamin D₃ caused a similar time-dependent antidepressant-like effect in male and female mice, suggesting that this behavioral response in the tail suspension test might not be affected by sex differences. Vitamin D₃ administration for 21 days, but not for 7 days or 1 h, augmented BDNF levels in the hippocampus and prefrontal cortex of mice. No effects on phospho-CREB/CREB levels were detected in the hippocampus and prefrontal cortex after chronic vitamin D₃ administration. Additionally, vitamin D₃ increased TrkB, GluA1, and PSD-95 levels in the prefrontal cortex, but not in the hippocampus. Furthermore, an upregulation of synapsin level was observed in both brain regions after vitamin D₃ administration. These findings reinforce and extend the notion that vitamin D₃ is effective to produce antidepressant-like responses in male and female mice and provide novel evidence that this effect could be associated with BDNF/TrkB-related synaptic protein synthesis. Finally, vitamin D₃ could be a feasible nutritional strategy for the management of depression.