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: Y Chen, C P Curran, D W Nebert, K V Patel, M T Williams, C V Vorhees
• Journal: Genes, brain, and behavior (Genes Brain Behav) Vol. 11 Issue 3 Pg. 269-77 (Apr 2012) ISSN: 1601-183X [Electronic] England
• PMID: 22296218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Chemical References

• L-Gulonolactone Oxidase
• Ascorbic Acid

Topics

• Animals
• Animals, Newborn
• Ascorbic Acid (genetics)
• Ascorbic Acid Deficiency (enzymology, genetics, physiopathology)
• Behavior, Animal (physiology)
• Disease Models, Animal
• Female
• L-Gulonolactone Oxidase (deficiency, genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Pregnancy