Division of Medical Sciences, Island Medical Program, University of Victoria, Canada.
Brain Res. 2011 Aug 11;1406:84-105. doi: 10.1016/j.brainres.2011.06.040. Epub 2011 Jun 23.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of CAG repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairments. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, although other regions including the hippocampus are also affected. In this review we discuss the different mouse models of HD, and how the process of neurogenesis in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) is affected in each. Deficits in adult hippocampal neurogenesis have been repeatedly shown in different genetic models of HD, raising the possibility that an impairment of the neurogenic process might underlie some of the cognitive deficits associated with this neurodegenerative disorder. On the other hand, an increase in SVZ neurogenesis has been observed in human HD brains while no differences in SVZ cell proliferation have been detected in the mouse models. In this review we will discuss the discrepancies between these findings as well as the several mechanisms that might contribute to a dysregulation of adult neurogenesis in HD. Finally, we will provide an overview of the various therapeutic strategies aimed at stimulating the endogenous neurogenic capacity that have been tested in HD genetic models. Ultimately, the insights obtained from these and future studies will greatly improve our understanding of the cognitive impairment characteristic of HD.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，由 HD 基因中 CAG 重复序列的不稳定扩增引起。其症状包括认知功能障碍和严重的运动障碍。神经病理学的特征是神经元丧失，主要发生在纹状体和皮层，但其他区域，包括海马体，也受到影响。在这篇综述中，我们讨论了不同的 HD 小鼠模型，以及神经发生过程在每个模型中的海马齿状回（DG）和侧脑室下区（SVZ）是如何受到影响的。在不同的 HD 遗传模型中，成年海马神经发生缺陷已被反复证明，这增加了神经发生过程受损可能是与这种神经退行性疾病相关的一些认知缺陷的基础的可能性。另一方面，在人类 HD 大脑中观察到 SVZ 神经发生增加，而在小鼠模型中未检测到 SVZ 细胞增殖的差异。在这篇综述中，我们将讨论这些发现之间的差异，以及可能导致 HD 中成年神经发生失调的几种机制。最后，我们将概述旨在刺激 HD 遗传模型中内源性神经生成能力的各种治疗策略。最终，从这些和未来的研究中获得的见解将极大地提高我们对 HD 特征性认知障碍的理解。
