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首页> 外文期刊>The European Journal of Neuroscience >Phenotypic expression of the targeted null-mutation in the dopamine transporter gene varies as a function of the genetic background.
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Phenotypic expression of the targeted null-mutation in the dopamine transporter gene varies as a function of the genetic background.

机译:多巴胺转运蛋白基因中靶向无效突变的表型表达随遗传背景而变化。

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摘要

Abstract The dopamine transporter (DAT) plays a critical role in calibrating the duration and intensity of dopamine (DA) neurotransmission. Mice in which the DAT gene has been genetically deleted exhibit constitutively high levels of extrasynaptic DA and spontaneous hyperactivity. Numerous studies have characterized the adaptive molecular, physiological, and behavioural consequences of abnormal DA neurotransmission in these mice. In order to determine the genetic background contribution to these phenotypes, the DAT mutation was transferred on C57BL/6JOrl (B6) or DBA/2JOrl (D2) inbred backgrounds for more than ten generations of back-crossing to derive three B6-, D2-, and B6xD2(F(1))-DAT strains. We observed that the genetic background dramatically affects phenotypes previously reported on DAT knockout (KO) mice. Depending on the genetic background, it was possible to restore survival, growth rate and ability to lactate. Interactions with the genetic background were found to modulate both quantitative and qualitative patterns of novelty-driven spontaneous hyperactivity. The paradoxical calming effect of cocaine was observed for all DAT-KO mice. However, the genetic background influenced individual threshold responses to both locomotor and rewarding effects of cocaine. These findings reveal the extent of phenotypic variation associated with the DAT mutation. They also provide concrete arguments against the assumption that the normal function of a gene can be inferred directly from its mutant phenotype.
机译:摘要多巴胺转运蛋白(DAT)在校准多巴胺(DA)神经传递的持续时间和强度中起着至关重要的作用。 DAT基因已被基因删除的小鼠表现出组成性高水平的突触外DA和自发性过度活跃。大量研究已经表征了这些小鼠中异常DA神经传递的适应性分子,生理和行为后果。为了确定遗传背景对这些表型的贡献,将DAT突变转移到C57BL / 6JOrl(B6)或DBA / 2JOrl(D2)近交背景上进行了十代以上的回交,以衍生出三个B6-,D2-和B6xD2(F(1))-DAT菌株。我们观察到遗传背景极大地影响了以前在DAT基因敲除(KO)小鼠上报道的表型。根据遗传背景,可以恢复存活率,生长速率和乳酸能力。发现与遗传背景的相互作用可调节新颖性驱动的自发性活动过度的定量和定性模式。在所有DAT-KO小鼠中都观察到可卡因的自相矛盾的镇定作用。然而,遗传背景影响了可卡因对运动和奖励作用的个体阈值响应。这些发现揭示了与DAT突变相关的表型变异的程度。他们还提供了反对这一假设的具体论点,即基因的正常功能可以直接从其突变表型推断出来。

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