Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.
Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.
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DOI：
10.1111/j.1601-183x.2011.00762.x
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Vorhees CV
中科院分区：
文献类型：
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作者：
Chen Y;Curran CP;Nebert DW;Patel KV;Williams MT;Vorhees CV
使用氧气进行有氧呼吸的生物体需要抗氧化剂来平衡代谢过程中反应氧的产生。包括人类和其他灵长类动物在内的多个物种的编码 L-古洛糖酸-γ-内酯氧化酶的 GULO 基因发生突变； GULO 是抗坏血酸（一种重要的细胞抗氧化剂）生物合成中的限速酶。缺乏合成维生素 C 能力的动物在不补充膳食的情况下会患坏血病。 Gulo(−/−)基因敲除小鼠需要口服补充维生素C；如果没有这种补充，动物会在几周内死于坏血病。众所周知，维生素 C 在大脑中含量最丰富，被认为在神经保护、神经传递和神经调节中发挥着重要作用。因此，我们假设 Gulo(−/−) 基因敲除小鼠中抗坏血酸缺乏可能导致异常的行为表型。我们确定了饮用水中抗坏血酸的含量（220 ppm），这是在大脑中产生慢性低抗坏血酸状态所必需的，但临床上，小鼠在产后 100 天内表现出健康状态，此时所有行为表型测试均已完成。与 Gulo(+/+) 野生型同窝小鼠相比，缺乏抗坏血酸的 Gulo(−/−) 小鼠在其环境中移动的活跃度较低；在一些测试中，这些小鼠在水中游得更慢，这与轻度运动缺陷一致。我们没有发现任何认知、焦虑或感觉运动门控问题的证据。尽管不太活跃，Gulo(−/−) 小鼠对多巴胺能激动剂甲基苯丙胺表现出过度活跃。不正常的运动，加上对多巴胺激动剂的过敏，表明发育性抗坏血酸缺乏导致长期纹状体功能障碍。
Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reaction 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 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(−/−) knockout 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.