Maternal vitamin D deficiency during pregnancy impaired offspring's spatial learning and memory ability: Insights into the role of the CaMKK2/AMPK/FoxO3a pathway.

Vitamin D deficiency (VDD) is a pressing global health concern, with pregnant women being identified as a high-risk population for VDD. Our previous study demonstrated that maternal VDD diet impaired placental development. Here, we aimed to investigate the effects of maternal VDD diet during pregnancy on offspring's spatial learning and memory ability. Our results showed that maternal VDD diet resulted in a decreased vitamin D levels in dams and their offspring, reduced offspring's body length and body weight, delayed offspring's nerve reflex behavior and impaired offspring's spatial learning and memory ability in Y maze and Morris water maze tests. Moreover, maternal VDD diet caused offspring's neuronal damage and loss, decreased the expressions of neurotrophic factors. While, maternal vitamin D supplementation during pregnancy has positive improvement on the above indexes, and with the most obvious in first trimester supplement group. Moreover, proteomic analysis of the offspring's hippocampal tissues was conducted to explore relative molecular mechanisms. Results showed that maternal VDD diet overactivated CaMKK2/AMPK/FoxO3a signaling pathway. While, CaMKK2 inhibitor STO-609 attenuated VDD-induced neuronal apoptosis and necrosis in vitro. Consistantly, maternal vitamin D supplementation during pregnancy also inhibited the overactivation of CaMKK2/AMPK/FoxO3a pathway. In conclusion, the present study provided novel insights into the mechanisms of maternal VDD on offspring's spatial learning and memory ability.