Title: Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.

Authors: Chen, Y; Curran, C P; Nebert, D W; Patel, K V; Williams, M T; Vorhees, C V

Published In Genes Brain Behav, (2012 Apr)

Abstract: Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reactive oxygen species during metabolic processes. Various species--including humans and other primates--suffer mutations in the GULO gene encoding L-gulono-γ-lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo-/- knockout (KO) mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo-/- KO mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo+/+ wild-type littermates, ascorbate-deficient Gulo-/- mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo-/- mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction.

PubMed ID: 22296218

MeSH Terms: Animals; Animals, Newborn; Ascorbic Acid Deficiency/enzymology*; Ascorbic Acid Deficiency/genetics*; Ascorbic Acid Deficiency/physiopathology; Ascorbic Acid/genetics; Behavior, Animal/physiology*; Disease Models, Animal; Female; L-Gulonolactone Oxidase/deficiency*; L-Gulonolactone Oxidase/genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Pregnancy