Quirion Jade G, Parsons Matthew P
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
Front Cell Neurosci. 2019 Jul 17;13:326. doi: 10.3389/fncel.2019.00326. eCollection 2019.
Huntington disease (HD) is an inherited neurodegenerative disease characterized by a clinical triad of motor, psychiatric and cognitive symptoms. HD is caused by a CAG repeat expansion in the gene encoding the huntingtin protein. Homozygosity for the HD-causing mutation is extremely rare; thus, the majority of HD patients express the mutant huntingtin protein in addition to reduced levels of the non-pathogenic huntingtin protein. Deficits in synaptic plasticity, including hippocampal long-term potentiation (LTP), have been identified in various mouse models of HD and are thought to contribute to the debilitating cognitive symptoms associated with the disease. However, the bulk of these studies used N-terminal fragment or homozygous knock-in mouse models of HD at symptomatic ages, and our understanding of the onset and progression of synaptic plasticity deficits in the HD brain is lacking. To better understand the time-course of synaptic plasticity deficits in HD, as well as the impact of heterozygous and homozygous huntingtin mutations, we quantified basal synaptic connectivity, presynaptic release probability, presynaptically mediated post-tetanic potentiation (PTP) and postsynaptically mediated LTP at presymptomatic, early symptomatic and late symptomatic ages in heterozygous and homozygous Q175FDN knock-in HD mice. Our results demonstrate clear age-dependent effects of the HD-causing mutation on both short and long-term plasticity that generally emerge earlier in homozygous mice. Interestingly, deficits in presynaptic short-term plasticity were more closely linked to disease progression than deficits in postsynaptic LTP, and heterozygous mice were more susceptible to an LTP deficit when induced by high frequency stimulation compared to theta burst stimulation. To the best of our knowledge, the present study represents the most thorough characterization to date of the onset and progression of hippocampal synaptic plasticity deficits in a mouse model of HD, and should prove valuable to future studies exploring cellular mechanisms underlying the debilitating cognitive decline in HD.
亨廷顿舞蹈症（HD）是一种遗传性神经退行性疾病，其临床特征为运动、精神和认知症状三联征。HD由编码亨廷顿蛋白的基因中CAG重复序列扩增引起。导致HD的突变纯合子极为罕见；因此，大多数HD患者除了非致病性亨廷顿蛋白水平降低外，还表达突变型亨廷顿蛋白。在HD的各种小鼠模型中已发现突触可塑性缺陷，包括海马长时程增强（LTP），并且认为这些缺陷导致了与该疾病相关的使人衰弱的认知症状。然而，这些研究大多使用有症状年龄的HD的N端片段或纯合敲入小鼠模型，我们对HD大脑中突触可塑性缺陷的发生和进展缺乏了解。为了更好地了解HD中突触可塑性缺陷的时间进程，以及杂合和纯合亨廷顿突变的影响，我们在杂合和纯合Q175FDN敲入HD小鼠的无症状、早期有症状和晚期有症状年龄阶段，对基础突触连接性、突触前释放概率、突触前介导的强直后增强（PTP）和突触后介导的LTP进行了量化。我们的结果表明，导致HD的突变对短期和长期可塑性都有明显的年龄依赖性影响，这些影响通常在纯合小鼠中出现得更早。有趣的是，突触前短期可塑性缺陷比突触后LTP缺陷与疾病进展的联系更紧密，并且与theta爆发刺激相比，高频刺激诱导时杂合小鼠更容易出现LTP缺陷。据我们所知，本研究是迄今为止对HD小鼠模型中海马突触可塑性缺陷的发生和进展最全面的表征，并且应该对未来探索HD中使人衰弱的认知衰退潜在细胞机制的研究有价值。
