Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice.
Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice.
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DOI：
10.1016/j.nbd.2013.08.009
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发表时间：
2013-12
影响因子：
6.1
通讯作者：
Reiner A
中科院分区：
文献类型：
--
作者：
Deng YP;Wong T;Bricker-Anthony C;Deng B;Reiner A
运动减慢、前脑白质丢失和纹状体萎缩已被报道在显性纹状体神经元丧失之前表现为亨廷顿病(HD)。我们在一只遗传上精确的HD模拟杂合子Q140 HD敲入小鼠中进行了详细的光镜和EM研究，以检查纹状体神经元丢失之前皮质纹状体和丘脑纹状体终末丢失是这些先兆HD异常的基础的可能性。在我们的研究中，我们使用VGLUT1和VGLUT2免疫标记技术在纹状体投射神经元病理之前的第一年分别检测了背外侧(运动)纹状体中的皮质纹状体和丘脑纹状体终末。VGLUT1+轴棘皮质纹状体终末约占纹状体兴奋性终末的55%，VGLUT2+轴棘丘脑纹状体终末约占35%，其余为VGLUT1+和VGLUT2+轴突终末。在Q140小鼠中，在1个月龄时已经观察到VGLUT2+轴树突状丘脑纹状体终末显著不足40%，轴棘丘脑纹状体终末缺失20%，但VGLUT1+终末数量正常。在Q140小鼠中，VGLUT2+丘脑纹状体轴棘终末20%的缺失在4个月和12个月时持续存在，VGLUT1+皮质纹状体终末在12个月时又有30%的缺失。Q140小鼠丘脑纹状体轴棘终末的早期和持续性缺陷可能反映了发育缺陷，这种对纹状体的兴奋性驱动的贫乏可能有助于解释Q140小鼠和先证性HD的早期运动缺陷。Q140小鼠1岁时皮质纹状体终末的丢失与其他小鼠模型进展早期皮质纹状体终末丢失的证据一致，可以解释晚期先兆HD患者可测量的运动迟缓和纹状体白质丢失。
Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington’s disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals was already observed at 1 month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12 months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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