Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor
Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor
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在过度表达胶质细胞系源性神经营养因子的转基因小鼠中发现纹状体低多巴胺表型
DOI：
10.1016/j.neulet.2017.06.005
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发表时间：
2017
影响因子：
2.5
通讯作者：
Nawa H
中科院分区：
文献类型：
--
作者：
Sotoyama H;Iwakura Y;Oda K;Sasaoka T;Takei N;Kakita A;Enomoto H;Nawa H
胶质细胞源性神经营养因子(GDNF)对玻璃体多巴胺能神经元的发育和维持具有正向调节作用。然而，GDNF信号对脑多巴胺系统的活体影响还存在争议，而且还没有完全确定。为了解决这个问题，我们分析了在glialGfAppromoter控制下过表达GDNF的转基因小鼠的多巴胺能表型。与野生型相比，GDNF转基因小鼠大脑中GDNF蛋白和磷酸化RET受体的水平更高。然而，转基因小鼠纹状体中酪氨酸羟化酶(TH)、多巴胺及其代谢物高香草酸的水平降低。TH的降低似乎发生在出生后发育期间。免疫组织化学显示转基因小鼠纹状体TH密度降低，未见明显的神经变性迹象。与这些神经化学特征一致的是，转基因小鼠纹状体内细胞外多巴胺的基础水平和高K+诱导的多巴胺外流减少。此外，我们还探讨了GDNF过表达对运动行为的影响。与野生型小鼠相比，GDNF转基因小鼠表现出较低的刻板印象和在新环境中的饲养。这些结果表明，GDNF在脑星形胶质细胞中的慢性过表达对黑质纹状体多巴胺代谢和神经传递产生相反的影响。
Glial cell line-derived neurotrophic factor (GDNF) positively regulates the development and maintenance ofin vitrodopaminergic neurons. However, thein vivoinfluences of GDNF signals on the brain dopamine system are controversial and not fully defined. To address this question, we analyzed dopaminergic phenotypes of the transgenic mice that overexpress GDNF under the control of the glialGfappromoter. Compared with wild-type, the GDNF transgenic mice contained higher levels of GDNF protein and phosphorylated RET receptors in the brain. However, there were reductions in the levels of tyrosine hydroxylase (TH), dopamine, and its metabolite homovanillic acid in the striatum of transgenic mice. The TH reduction appeared to occur during postnatal development. Immunohistochemistry revealed that striatal TH density was reduced in transgenic mice with no apparent signs of neurodegeneration. In agreement with these neurochemical traits, basal levels of extracellular dopamine and high K+-induced dopamine efflux were decreased in the striatum of transgenic mice. We also explored the influences of GDNF overexpression on lomomotor behavior. GDNF transgenic mice exhibited lower stereotypy and rearing in a novel environment compared with wild-type mice. These results suggest that chronic overexpression of GDNF in brain astrocytes exerts an opposing influence on nigrostriatal dopamine metabolism and neurotransmission.