Homozygote inositol transporter knockout mice show a lithium-like phenotype
Homozygote inositol transporter knockout mice show a lithium-like phenotype
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DOI：
10.1111/j.1399-5618.2007.00546.x
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发表时间：
2008-06-01
影响因子：
5.4
通讯作者：
Belmaker, Robert H.
中科院分区：
文献类型：
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作者：
Bersudsky, Yuly;Shaldubina, Alona;Belmaker, Robert H.
目的：锂抑制肌醇单磷酸酶并降低肌醇转运蛋白功能。为了确定这些机制中的一种或多种是否可能是锂的行为效应的基础，我们研究了肌醇转运蛋白基因敲除小鼠。我们以前报道过，杂合子敲除小鼠脑肌醇减少15-37%，在Porsolt强迫游泳试验中没有毛果芸香碱敏感性或抗抑郁药样行为的异常。我们现在报告的研究纯合子肌醇转运蛋白基因敲除mice.Methods：纯合子敲除小鼠被拯救的2%肌醇补充到饮用水的母鼠通过怀孕和哺乳。采用聚合酶链反应和琼脂糖电泳进行基因分型。用气相色谱法测定脑游离肌醇水平。通过旋转棒测试评估运动活性和协调性。在锂-匹罗卡品癫痫发作模型中锂的作用和在Porsolt强迫游泳试验模型中抑郁症的小鼠的行为进行了研究。结果：在纯合子基因敲除小鼠中，游离肌醇水平减少了55%，在额叶皮层和60%，在海马。通过旋转棒测试，在体重或运动协调方面没有差异。他们表现出类似的锂处理的动物在模型中的匹鲁卡品癫痫发作和在Porsolt强迫游泳测试modelofdepression.Conclusions：减少脑肌醇超过15-37%可能需要引起锂样神经行为的影响。
Objective: Lithium inhibits inositol monophosphatase and also reduces inositol transporter function. To determine if one or more of these mechanisms might underlie the behavioral effects of lithium, we studied inositol transporter knockout mice. We previously reported that heterozygous knockout mice with reduction of 15-37% in brain inositol had no abnormalities of pilocarpine sensitivity or antidepressant-like behavior in the Porsolt forced swim test. We now report on studies of homozygous inositol transporter knockout mice.Methods: Homozygote knockout mice were rescued by 2% inositol supplementation to the drinking water of the dam mice through pregnancy and lactation. Genotyping was carried out by polymerase chain reaction followed by agarose electrophoresis. Brain free myo-inositol levels were determined gas-chromatographically. Motor activity and coordination were assessed by the rotarod test. Behavior of the mice was studied in lithium-pilocarpine seizure models for lithium action and in the Porsolt forced swim test model for depression.Results: In homozygote knockout mice, free inositol levels were reduced by 55% in the frontal cortex and by 60% in the hippocampus. There were no differences in weight or motor coordination by the rotarod test. They behaved similarly to lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced swimming test model of depression.Conclusions: Reduction of brain inositol more than 15-37% may be required to elicit lithium-like neurobehavioral effects.