Differential loss of thalamostriatal and corticostriatal input to striatal projection neuron types prior to overt motor symptoms in the Q140 knock-in mouse model of Huntington's disease.
Differential loss of thalamostriatal and corticostriatal input to striatal projection neuron types prior to overt motor symptoms in the Q140 knock-in mouse model of Huntington's disease.
复制标题
在亨廷顿氏病的Q140敲门小鼠模型中，丘脑纹状体和皮质纹状体输入对纹状体投射神经元类型的差异损失。
DOI：
10.3389/fnsys.2014.00198
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发表时间：
2014
影响因子：
3
通讯作者：
Reiner A
中科院分区：
文献类型：
--
作者：
Deng YP;Wong T;Wan JY;Reiner A
运动减慢和前脑白质丢失是亨廷顿病(HD)先于大量纹状体神经元丢失的先兆症状。这些发现提出了HD早期运动缺陷可能与纹状体兴奋性输入丢失有关的可能性。在先前的研究中，我们发现在杂合子Q140敲入的HD小鼠模型中，丘脑纹状体轴棘终末的丢失在4个月后明显，皮质纹状体轴棘终末的丢失在纹状体投射神经元病理之前的12个月明显。在本研究中，我们用免疫标记法识别丘脑纹状体(VGLUT2+)和皮质纹状体(VGLUT1+)轴突终末，并用D1受体免疫标记区分dSPN(D1+)和iSPN(D1−)突触靶标，以明确纹状体和皮质纹状体直接(DSPN)和间接(ISPN)途径纹状体投射神经元的终末丢失。我们发现，12个月龄时皮质纹状体终末的丢失更倾向于D1+脊椎，尤其是较小的终末，推测为脑内投射(IT)型。相比之下，间接通路D1−脊椎在同龄时轴棘终末几乎没有丢失。在4个月和12个月时，D1+和D1−脊椎的丘脑纹状体末端丢失是相似的。回归分析显示，在12个月时，D1+脊椎上VGLUT1+终末的丢失与开放领域运动参数的轻微下降有关。我们的总体结果增加了这样一种可能性，即丘脑和皮质对SPN的差异性输入丢失是人类HD的早期事件，其中对DSPN的皮质丢失尤其是对显性运动减慢有贡献。
Motor slowing and forebrain white matter loss have been reported in premanifest Huntington's disease (HD) prior to substantial striatal neuron loss. These findings raise the possibility that early motor defects in HD may be related to loss of excitatory input to striatum. In a prior study, we showed that in the heterozygous Q140 knock-in mouse model of HD that loss of thalamostriatal axospinous terminals is evident by 4 months, and loss of corticostriatal axospinous terminals is evident at 12 months, before striatal projection neuron pathology. In the present study, we specifically characterized the loss of thalamostriatal and corticostriatal terminals on direct (dSPN) and indirect (iSPN) pathway striatal projection neurons, using immunolabeling to identify thalamostriatal (VGLUT2+) and corticostriatal (VGLUT1+) axospinous terminals, and D1 receptor immunolabeling to distinguish dSPN (D1+) and iSPN (D1−) synaptic targets. We found that the loss of corticostriatal terminals at 12 months of age was preferential for D1+ spines, and especially involved smaller terminals, presumptively of the intratelencephalically projecting (IT) type. By contrast, indirect pathway D1− spines showed little loss of axospinous terminals at the same age. Thalamostriatal terminal loss was comparable for D1+ and D1− spines at both 4 and 12 months. Regression analysis showed that the loss of VGLUT1+ terminals on D1+ spines was correlated with a slight decline in open field motor parameters at 12 months. Our overall results raise the possibility that differential thalamic and cortical input loss to SPNs is an early event in human HD, with cortical loss to dSPNs in particular contributing to premanifest motor slowing.