title: Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.
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.
authors.affiliation: Department of Environmental Health, Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: C P
authors.initials: CP
authors.lastname: Curran
authors.forename: D W
authors.initials: DW
authors.lastname: Nebert
authors.forename: K V
authors.initials: KV
authors.lastname: Patel
authors.forename: M T
authors.initials: MT
authors.lastname: Williams
authors.forename: C V
authors.initials: CV
authors.lastname: Vorhees
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001205:Ascorbic Acid / Q000235:genetics; D001206:Ascorbic Acid Deficiency / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D050544:L-Gulonolactone Oxidase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011247:Pregnancy
chemical_list: D050544:L-Gulonolactone Oxidase; D001205:Ascorbic Acid