Dopamine release is impaired in a mouse model of DYT1 dystonia
Dopamine release is impaired in a mouse model of DYT1 dystonia
复制标题
DOI：
10.1111/j.1471-4159.2007.04590.x
复制
发表时间：
2007-08-01
影响因子：
4.7
通讯作者：
Standaert, David G.
中科院分区：
文献类型：
--
作者：
Balcioglu, Aygul;Kim, Mee-Ohk;Standaert, David G.
早发性扭转肌张力障碍是遗传性原发性肌张力障碍最常见的形式，由编码TorsinA蛋白的TOR1A基因突变引起。这种形式的肌张力障碍被称为DYT1。我们使用了DYT1肌张力障碍的转基因小鼠模型[人突变型(HMT)1小鼠]来检测突变的人TorsinA蛋白对纹状体多巴胺能功能的影响。纹状体组织多巴胺(DA)和代谢产物的高效液相分析表明，hMT1小鼠和它们的非转基因后代之间没有差异。用体外放射自显影技术研究了膜DA转运体的配体[H-3]mazindol和囊泡单胺转运体的配体[H-3]二氢四苯并嗪对突触前DA转运体的影响。纹状体DA转运体和囊泡单胺转运体结合部位的密度无明显差异。用D-1类受体的配体[H-3]SCH-23390、D-2类受体的配体[H-3]YM-09151-2和D-2类受体的配体[H-3]SCH-09151-2研究突触后受体。同样，这些配体的纹状体结合位点密度也没有差异。利用清醒动物的体内微透析，我们研究了基础和苯丙胺刺激的纹状体细胞外多巴胺水平。基础细胞外多巴胺水平相似，但hMT1小鼠对苯丙胺的反应明显减弱(253+/-71%vs.561+/-132%，p<；0.05，双向方差分析)。这些观察表明，引起DYT1肌张力障碍的TorsinA蛋白突变可能干扰DA的运输或释放，但不改变突触前转运体或突触后DA受体。观察到的DA释放缺陷可能与先前在这个转基因小鼠模型中记录的运动学习异常有关，并可能导致人类疾病的临床症状。
Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [H-3]mazindol, a ligand for the membrane DA transporter, and [H-3]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using [H-3]SCH-23390, a ligand for D-1 class receptors, [H-3]YM-09151-2 and a ligand for D-2 class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way ANOVA). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or postsynaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.