Profound neuronal plasticity in response to inactivation of the dopamine transporter
Profound neuronal plasticity in response to inactivation of the dopamine transporter
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DOI：
10.1073/pnas.95.7.4029
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发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Caron, MG
中科院分区：
文献类型：
--
作者：
Jones, SR;Gainetdinov, RR;Caron, MG
多巴胺转运蛋白（DAT）在调节中枢神经系统多巴胺神经传递的持续时间和强度方面起着重要作用。我们使用了一种DAT基因被基因删除的小鼠来鉴定DAT的稳态作用。我们发现，DAT的去除大大缩短了细胞外多巴胺的寿命（300倍），在神经传递的时间框架内，除了扩散没有其他过程可以补偿DAT的缺乏，DAT的缺乏产生广泛的适应性变化来控制多巴胺神经传递。尽管缺乏清除机制，但由于含量减少95%和释放减少75%，多巴胺细胞外水平仅比对照动物高5倍。特别地，尽管酪氨酸羟化酶水平降低90%，多巴胺合成速率加倍，并且降解显著增强。DAT不仅控制细胞外多巴胺信号的持续时间，而且在调节突触前多巴胺稳态中起关键作用。有趣的是，在缺乏DAT的小鼠中观察到的多巴胺缺乏但功能过度活跃的神经传递模式的转变可能代表了长期精神兴奋剂滥用导致的神经元可塑性的一个极端例子。
The dopamine transporter (DAT) plays an important role in calibrating the duration and intensity of dopamine neurotransmission in the central nervous system, We have used a strain of mice in which the gene for the DAT has been genetically deleted to identify the DAT's homeostatic role. We find that removal of the DAT dramatically prolongs the lifetime (300 times) of extracellular dopamine, Within the time frame of neurotransmission, no other processes besides diffusion can compensate for the lack of the DAT, and the absence of the DAT produces extensive adaptive changes to control dopamine neurotransmission. Despite the absence of a clearance mechanism, dopamine extracellular levels were only 5 times greater than control animals due to a 95% reduction in content and a 75% reduction in release, Paradoxically, dopamine synthesis rates are doubled despite a decrease of 90% in the levels of tyrosine hydroxylase and degradation is markedly enhanced, Thus, the DAT not only controls the duration of extracellular dopamine signals but also plays a critical role in regulating presynaptic dopamine homeostasis. It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse.