Department of Psychiatry and Brain Research Centre, University of British Columbia, Vancouver, Canada.
Neuroscience. 2011 Dec 15;198:252-73. doi: 10.1016/j.neuroscience.2011.08.052. Epub 2011 Aug 27.
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, that is, early vs. 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.
亨廷顿病（HD）是一种进行性、致命的神经疾病，由亨廷顿基因编码区 CAG（谷氨酰胺）重复扩展引起。迄今为止，尚无治愈方法，但在理解病理生理机制方面取得了重大进展。特别是，HD 的遗传动物模型对于阐明行为和生理改变的进展至关重要，这在使用经典神经毒素模型时是不可能的。我们的研究小组率先使用转基因 HD 小鼠来研究纹状体神经元功能障碍和退化的兴奋性毒性假说，以及纹状体和大脑皮层兴奋和抑制的改变。在这篇综述中，我们重点关注遗传 HD 小鼠模型中纹状体中型棘突（MSNs）和皮质锥体神经元的突触和受体改变。我们证明了一系列复杂的、具有区域特异性和时间依赖性的改变。特别是，许多变化是双向的，取决于疾病进展的程度，即早期与晚期，以及所检查的区域。早期的突触功能障碍表现为纹状体中谷氨酸释放的失调，随后皮质和纹状体之间逐渐失去连接。还阐明了改变的谷氨酸释放对起源于直接和间接途径的 MSNs 的不同影响，令人意外的是，疾病早期就涉及到直接纹状体途径的细胞。此外，我们还回顾了早期 N-甲基-D-天冬氨酸受体（NMDAR）功能障碍导致 extrasynaptic 受体敏感性增强的证据，以及 GluN2B 亚基的关键作用。HD 晚期的一些改变可能是为了应对早期的突触和受体功能障碍而设计的补偿机制。主要发现表明，HD 治疗需要根据疾病进展阶段进行设计，并应考虑区域差异。
