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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior
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Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

机译：消融表达D1多巴胺受体的细胞会导致癫痫发作，肌张力障碍，活动过度和口腔行为受损的小鼠

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Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P. and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electro-graphically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a+ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons.
机译：亨廷顿舞蹈病的特征是纹状体投射神经元死亡。我们使用Cre / Lox转基因方法来生成动物模型，其中D1多巴胺受体（Drd1a）+细胞在出生后的大脑中逐渐消融。纹状体Drd1a，物质P.和强啡肽的表达逐渐丧失，而D2多巴胺受体（Drd2）和脑啡肽的表达上调。磁共振波谱分析表明，纹状体胆碱/肌酸的比率较早升高，这一发现与广泛的反应性纹状体星形胶质增生有关。顺序MRI证实纹状体体积逐渐减少，继发性心室扩大被证实是由于纹状体细胞丢失所致。突变小鼠的步态和轮转能力正常，但表现出后肢肌张力障碍，运动亢进和经处理诱发的电子照相证实的自发性癫痫发作。伦理学评估发现，筛分和咀嚼的口腔行为增加了饲养和损害。与边缘性癫痫发作相一致，在海马齿状回中观察到细胞丢失，星形胶质细胞增生，小胶质细胞增生和强啡肽表达下调。这项研究特别暗示Drd1a +细胞丢失与尾巴悬吊后肢肌张力障碍，活动过度和口腔功能异常。后者可能与在亨廷顿舞蹈病中观察到的言语和吞咽障碍以及舌头运动无力的经典症状有关。另外，这项研究的发现支持了Drd1a和Drd2在纹状体投射神经元上分离的观点。

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