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利用多巴胺 -1 受体启动子过表达钾通道 Kir2.3 可选择性抑制纹状体神经元。

Over-expression of the potassium channel Kir2.3 using the dopamine-1 receptor promoter selectively inhibits striatal neurons.

作者信息

Falk T, Xie J Y, Zhang S, Kennedy J, Bennett J, Yool A J, Sherman S J

机构信息

Department of Neurology, The University of Arizona, Arizona Health Sciences Center, Tucson, AZ 85724, USA.

出版信息

Neuroscience. 2008 Jul 31;155(1):114-27. doi: 10.1016/j.neuroscience.2008.04.075. Epub 2008 May 16.

Abstract

Dysfunction of basal ganglia circuits underlies a variety of movement disorders and neuropsychiatric conditions. Selective control of the electrical activity of striatal outflow pathways by manipulation of ion channel function presents a novel therapeutic approach. Toward this end, we have constructed and studied in vitro an adenoviral gene transfer vector that employs the promoter region of the dopamine-1 receptor to drive expression of the inward rectifier K(+) channel Kir2.3. The use of this neuronal promoter confers cell-type specificity and a physiological level of trans-gene expression in rat primary striatal cultures. The electrophysiological properties were confirmed in transfected human embryonic kidney cells, in which an inwardly-rectifying, Cs(+)-sensitive current was measured by voltage clamp. Current clamp studies of transduced striatal neurons demonstrated an increase in the firing threshold, latency to first action potential and decrease in neuronal excitability. Neurotoxin-induced activation of c-Fos, a marker of neuronal activity, was blocked in transduced neurons indicating that the decrease in electrical excitability was physiologically significant. When used in vivo, this strategy may have the potential to positively impact movement disorders by selectively changing activity of neurons belonging to the direct striatal pathway, characterized by the expression of dopamine-1 receptors.

摘要

基底神经节回路功能障碍是多种运动障碍和神经精神疾病的基础。通过操纵离子通道功能来选择性控制纹状体流出通路的电活动,提供了一种新的治疗方法。为此,我们构建并在体外研究了一种腺病毒基因转移载体,该载体利用多巴胺-1受体的启动子区域来驱动内向整流钾通道Kir2.3的表达。使用这种神经元启动子可赋予细胞类型特异性,并在大鼠原代纹状体培养物中实现转基因表达的生理水平。在转染的人胚肾细胞中证实了其电生理特性,通过电压钳测量到了内向整流、对Cs(+)敏感的电流。对转导的纹状体神经元进行电流钳研究表明,放电阈值增加,首次动作电位潜伏期延长,神经元兴奋性降低。神经毒素诱导的神经元活动标记物c-Fos的激活在转导的神经元中被阻断,这表明电兴奋性的降低具有生理意义。当在体内使用时,这种策略可能有潜力通过选择性改变属于直接纹状体通路、以多巴胺-1受体表达为特征的神经元的活动,对运动障碍产生积极影响。

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