Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.
Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.
复制标题
DOI：
10.1016/j.neuroscience.2011.08.052
复制
发表时间：
2011-12-15
期刊：
影响因子：
3.3
通讯作者：
Levine, M. S.
中科院分区：
文献类型：
--
作者：
Raymond, L. A.;Andre, V. M.;Cepeda, C.;Gladding, C. M.;Milnerwood, A. J.;Levine, M. S.
关键词：
亨廷顿病(HD)是一种进行性的、致命的神经系统疾病，由亨廷顿基因编码区的CAG(谷氨酰胺)重复序列扩大引起。到目前为止，还没有治愈的方法，但在了解病理生理机制方面取得了很大进展。特别是，HD的遗传动物模型在阐明行为和生理变化的进展方面发挥了重要作用，这是使用经典神经毒素模型所不可能做到的。我们的团队率先使用转基因HD小鼠来检验纹状体神经元功能障碍和变性的兴奋毒性假说，以及纹状体和大脑皮层兴奋和抑制的变化。在这篇综述中，我们重点介绍了遗传性HD小鼠模型中纹状体中型棘神经元和皮质锥体神经元的突触和受体的变化。我们演示了一系列复杂的变化，这些变化是特定于地区和时间相关的。特别是，许多变化是双向的，这取决于疾病进展的程度，即早期和晚期，也取决于检查的区域。早期突触功能障碍表现为纹状体谷氨酸释放紊乱，继而皮质与纹状体逐渐断开。谷氨酸释放的改变对起源于直接途径和间接途径的MSN的不同影响也被阐明，意外的发现直接纹状体途径的细胞参与了疾病的早期过程。此外，我们回顾了早期N-甲基-D-天冬氨酸受体(NMDAR)功能障碍导致突触外受体敏感性增强的证据，以及GluN2B亚单位的关键作用。晚期HD的一些改变可能是为应对早期突触和受体功能障碍而设计的代偿机制。主要研究结果表明，HD治疗需要根据疾病进展阶段进行设计，并应考虑地区差异。
Huntington’s disease (HD) is a progressive, fatal neurological condition caused by an expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. To date, there is no cure but great strides have been made to understand pathophysiological mechanisms. In particular, genetic animal models of HD have been instrumental in elucidating the progression of behavioral and physiological alterations, which had not been possible using classic neurotoxin models. Our groups have pioneered the use of transgenic HD mice to examine the excitotoxicity hypothesis of striatal neuronal dysfunction and degeneration, as well as alterations in excitation and inhibition in striatum and cerebral cortex. In this review, we focus on synaptic and receptor alterations of striatal medium-sized spiny (MSNs) and cortical pyramidal neurons in genetic HD mouse models. We demonstrate a complex series of alterations that are region-specific and time-dependent. In particular, many changes are bidirectional depending on the degree of disease progression, i.e., early versus late, and also on the region examined. Early synaptic dysfunction is manifested by dysregulated glutamate release in striatum followed by progressive disconnection between cortex and striatum. The differential effects of altered glutamate release on MSNs originating the direct and indirect pathways is also elucidated, with the unexpected finding that cells of the direct striatal pathway are involved early in the course of the disease. In addition, we review evidence for early N-methyl-D-aspartate receptor (NMDAR) dysfunction leading to enhanced sensitivity of extrasynaptic receptors and a critical role of GluN2B subunits. Some of the alterations in late HD could be compensatory mechanisms designed to cope with early synaptic and receptor dysfunctions. The main findings indicate that HD treatments need to be designed according to the stage of disease progression and should consider regional differences.
登录
查看更多内容
影响因子：
11.2
作者：
ALBIN, RL;REINER, A;YOUNG, AB
通讯作者：
YOUNG, AB
影响因子：
14.5
作者：
Bäckman, L;Robins-Wahlin, TB;Farde, L
通讯作者：
Farde, L
影响因子：
2.5
作者：
André, VM;Cepeda, C;Levine, MS
通讯作者：
Levine, MS
影响因子：
3.4
作者：
Andre, Veronique M.;Cepeda, Carlos;Levine, Michael S.
通讯作者：
Levine, Michael S.
影响因子：
4.1
作者：
Biolsi, Brigitte;Cif, Laura;Coubes, Philippe
通讯作者：
Coubes, Philippe