Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington's Disease.
Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington's Disease.
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DOI：
10.1371/journal.pone.0200626
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Luebke JI
中科院分区：
文献类型：
--
作者：
Goodliffe JW;Song H;Rubakovic A;Chang W;Medalla M;Weaver CM;Luebke JI
亨廷顿氏病（HD）是一种常染色体显性、进行性神经退行性疾病，由亨廷顿基因中CAG重复序列的有害扩增和神经毒性突变亨廷顿蛋白（mHTT）的产生引起。HD的关键病理特征是纹状体的严重变性和皮质体积的损失。HD早期间接通路（D2）中棘神经元（MSN）投射的最初丧失，随后在晚期直接通路（D1）投射的丧失对HD运动和认知功能障碍的轨迹具有重要意义，但尚未了解。HD的小鼠模型已经产生了关于mHTT毒性的作用和机制的重要信息;然而，这些模型是否概括了D1与D2 MSN的差异脆弱性尚不清楚。在这里，我们采用了12个月大的Q175+/- x D2-eGFP小鼠来检查D1与D2 MSN的详细结构和功能特性。虽然D1和D2 MSNs表现出增加的输入电阻，去极化静息膜电位和动作电位阈值，只有D1 MSNs表现出降低的基强度，动作电位振幅和频率的自发兴奋性突触后电流。此外，D1，而不是D2 MSN表现出显着的增殖变化，其树突状乔木和减少棘密度。免疫组织化学评估显示，没有损失的amatergic传入输入从皮质和皮质下来源到确定的D1和D2 MSN。受经验数据约束的计算模型预测，Q175+/- D1 MSN中增加的树突复杂性可能导致更大的树突过滤和从树突传播到索马的信号的衰减。总之，这些发现表明，到12个月时，D1和D2 MSN在这种重要的HD小鼠模型中对mHTT的存在表现出独特的反应。这进一步突出表明，需要将D1和D2 MSN的调查结果独立纳入HD模型。
Huntington’s Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by deleterious expansion of CAG repeats in the Huntingtin gene and production of neurotoxic mutant Huntingtin protein (mHTT). The key pathological feature of HD is a profound degeneration of the striatum and a loss of cortical volume. The initial loss of indirect pathway (D2) medium spiny neuron (MSN) projections in early stages of HD, followed by a loss of direct pathway (D1) projections in advanced stages has important implications for the trajectory of motor and cognitive dysfunction in HD, but is not yet understood. Mouse models of HD have yielded important information on the effects and mechanisms of mHTT toxicity; however, whether these models recapitulate differential vulnerability of D1 vs. D2 MSNs is unknown. Here, we employed 12-month-old Q175+/- x D2-eGFP mice to examine the detailed structural and functional properties of D1 vs. D2 MSNs. While both D1 and D2 MSNs exhibited increased input resistance, depolarized resting membrane potentials and action potential threshold, only D1 MSNs showed reduced rheobase, action potential amplitude and frequency of spontaneous excitatory postsynaptic currents. Furthermore, D1 but not D2 MSNs showed marked proliferative changes to their dendritic arbors and reductions in spine density. Immunohistochemical assessment showed no loss of glutamatergic afferent inputs from cortical and subcortical sources onto identified D1 and D2 MSNs. Computational models constrained by empirical data predict that the increased dendritic complexity in Q175+/- D1 MSNs likely leads to greater dendritic filtering and attenuation of signals propagating to the soma from the dendrites. Together these findings reveal that, by twelve months, D1 and D2 MSNs exhibit distinctive responses to the presence of mHTT in this important mouse model of HD. This further highlights the need to incorporate findings from D1 and D2 MSNs independently in the context of HD models.
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影响因子：
4.8
作者：
Ansari, Amir Mehdi;Ahmed, A. Karim;Matsangos, Aerielle E.;Lay, Frank;Born, Louis J.;Marti, Guy;Harmon, John W.;Sun, Zhaoli
通讯作者：
Sun, Zhaoli
影响因子：
11.2
作者：
ALBIN, RL;REINER, A;YOUNG, AB
通讯作者：
YOUNG, AB
DOI：
10.1523/jneurosci.2581-12.2012
发表时间：
2012-10-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Amatrudo JM;Weaver CM;Crimins JL;Hof PR;Rosene DL;Luebke JI
通讯作者：
Luebke JI
影响因子：
5.3
作者：
Cepeda, Carlos;Galvan, Laurie;Levine, Michael S.
通讯作者：
Levine, Michael S.
影响因子：
25
作者：
Aizman, O;Brismar, H;Aperia, A
通讯作者：
Aperia, A