Vitamin C and vitamin E double-deficiency increased neuroinflammation and impaired conditioned fear memory

Background: Vitamin C (L-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions. Methods: DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (−) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (−) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks. Results: The plasma VC and VE levels in DKO-CE (−) mice and VE level in WT-CE (−) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (−) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (−) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα F4/80, and Mcp-1, in the hippocampus of DKO-CE (−) mice. Conclusions: The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.