Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system
Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system
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DOI：
10.1016/j.neuroscience.2007.03.030
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发表时间：
2007-06-08
期刊：
影响因子：
3.3
通讯作者：
Clippen, E.
中科院分区：
文献类型：
--
作者：
Homberg, J. R.;Olivier, J. D. A.;Clippen, E.
5-羟色胺能信号参与许多神经生物学过程，5-羟色胺稳态失调与多种精神疾病和成瘾性疾病有关。在这里，我们描述了5-羟色胺转运体(SERT)基因敲除大鼠模型的功能特征，该模型是由N-乙基-N-亚硝脲(ENU)驱动的靶向选择性突变产生的。生化检测显示，纯合基因敲除(SERT-/-)大鼠SERT mRNA和功能蛋白完全缺失，杂合基因敲除大鼠SERT的表达和功能存在基因剂量依赖性的降低。结果发现，SERT-/-大鼠的5-羟色胺动态平衡受到严重影响：5-羟色胺组织水平和去极化诱导的5-羟色胺释放显著减少，海马区基础细胞外5-羟色胺水平增加九倍。有趣的是，我们发现色氨酸羟基酶和单胺氧化酶的体外活性没有补偿性变化，这两种酶分别参与5-羟色胺的合成和降解。同样，根据多巴胺和去甲肾上腺素转运体结合、单胺组织水平以及去极化诱导的多巴胺、去甲肾上腺素、谷氨酸和GABA的释放，在非5-羟色胺能系统中没有发现主要的适应。总之，SERT基因敲除大鼠的神经化学变化主要局限于5-羟色胺能系统，这使得这个新的大鼠模型对于研究扰乱5-羟色胺稳态的行为和神经生物学后果非常有用。(C)2007年IBRO。爱思唯尔有限公司出版。保留所有权利。
Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis. Biochemical characterization revealed that SERT mRNA and functional protein are completely absent in homozygous knockout (SERT-/-) rats, and that there is a gene dose-dependent reduction in the expression and function of the SERT in heterozygous knockout rats. As a result, 5-HT homeostasis was found to be severely affected in SERT-/- rats: 5-HT tissue levels and depolarization-induced 5-HT release were significantly reduced, and basal extracellular 5-HT levels in the hippocampus were ninefold increased. Interestingly, we found no compensatory changes in in vitro activity of tryptophan hydroxylase and monoamine oxidase, the primary enzymes involved in 5-HT synthesis and degradation, respectively. Similarly, no major adaptations in nonserotonergic systems were found, as determined by dopamine and noradrenaline transporter binding, monoamine tissue levels, and depolarization-induced release of dopamine, noradrenaline, glutamate and GABA. In conclusion, neurochemical changes in the SERT knockout rat are primarily limited to the serotonergic system, making this novel rat model potentially very useful for studying the behavioral and neurobiological consequences of disturbed 5-HT homeostasis. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.