Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Brain Research Institute, University of California-Los Angeles, Los Angeles, California 90095.
Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Brain Research Institute, University of California-Los Angeles, Los Angeles, California 90095
J Neurosci. 2018 May 16;38(20):4678-4694. doi: 10.1523/JNEUROSCI.0434-18.2018. Epub 2018 Apr 24.
The present study examined synaptic communication between direct and indirect output pathway striatal medium-sized spiny neurons (MSNs) and their target structures, the substantia nigra pars reticulata (SNr) and the external globus pallidus (GPe) in two mouse models of Huntington's disease (HD). Cre recombination, optogenetics, and whole-cell patch-clamp recordings were used to determine alterations in intrinsic and synaptic properties of SNr and GPe neurons from both male and female symptomatic R6/2 (>60 d) and presymptomatic (2 months) or symptomatic (10-12 months) YAC128 mice. Cell membrane capacitance was decreased, whereas input resistance was increased in SNr neurons from R6/2, but not YAC128 mice. The amplitude of GABAergic responses evoked by optogenetic stimulation of direct pathway terminals was reduced in SNr neurons of symptomatic mice of both models. A decrease in spontaneous GABA synaptic activity, in particular large-amplitude events, in SNr neurons also was observed. Passive membrane properties of GPe neurons were not different between R6/2 or YAC128 mice and their control littermates. Similarly, the amplitude of GABA responses evoked by activation of indirect pathway MSN terminals and the frequency of spontaneous GABA synaptic activity were similar in HD and control animals. In contrast, the decay time of the evoked GABA response was significantly longer in cells from HD mice. Interestingly, activation of indirect pathway MSNs within the striatum evoked larger-amplitude responses in direct pathway MSNs. Together, these results demonstrate differential alterations in responses evoked by direct and indirect pathway terminals in SNr and GPe leading to striatal output imbalance and motor dysfunction. Previous work on Huntington's disease (HD) focused on striatal medium-sized spiny neurons (MSNs) almost exclusively. Little is known about the effects that alterations in the striatum have on output structures of the direct and indirect pathways, the substantia nigra pars reticulata (SNr) and the external segment of the globus pallidus (GPe), respectively. We combined electrophysiological and optogenetic methods to examine responses evoked by selective activation of terminals of direct and indirect pathway MSNs in SNr and GPe neurons in two mouse models of HD. We show a differential disruption of synaptic communication between the direct and indirect output pathways of the striatum with their target regions leading to an imbalance of striatal output, which will contribute to motor dysfunction.
本研究在两种亨廷顿病（HD）小鼠模型中检查了纹状体中间神经元（MSN）的直接和间接输出通路之间的突触通讯及其靶结构，黑质网状部（SNr）和外苍白球（GPe）。使用 Cre 重组、光遗传学和全细胞膜片钳记录来确定来自雄性和雌性症状性 R6/2（>60d）和前症状性（2 个月）或症状性（10-12 个月）YAC128 小鼠的 SNr 和 GPe 神经元的内在和突触特性的改变。在 R6/2 小鼠的 SNr 神经元中，细胞膜电容减小，而输入电阻增加，但在 YAC128 小鼠中则没有。直接通路末端的光遗传学刺激引起的 GABA 能反应的幅度在两种模型的症状性小鼠的 SNr 神经元中降低。在 SNr 神经元中还观察到自发 GABA 突触活动，特别是大振幅事件的减少。R6/2 或 YAC128 小鼠及其对照同窝仔鼠之间的 GPe 神经元的被动膜特性没有差异。同样，间接通路 MSN 末端激活引起的 GABA 反应幅度和自发 GABA 突触活动的频率在 HD 和对照动物中相似。相比之下，HD 小鼠细胞中诱发 GABA 反应的衰减时间明显延长。有趣的是，纹状体中间接通路 MSN 的激活在直接通路 MSN 中引起更大幅度的反应。总之，这些结果表明，在 SNr 和 GPe 中，直接和间接通路末端引起的反应存在差异，导致纹状体输出失衡和运动功能障碍。以前关于亨廷顿病（HD）的工作几乎完全集中在纹状体中间神经元（MSN）上。关于纹状体的改变对直接和间接通路的输出结构，即黑质网状部（SNr）和外苍白球（GPe）的影响知之甚少。我们结合电生理和光遗传学方法，在两种 HD 小鼠模型中检查了选择性激活直接和间接通路 MSN 末端在 SNr 和 GPe 神经元中引起的反应。我们显示了纹状体的直接和间接输出通路与靶区之间的突触通讯的差异破坏，导致纹状体输出失衡，这将导致运动功能障碍。
