Florey Neuroscience Institutes, Melbourne Brain Centre, University of Melbourne, Melbourne, VIC 3010, Australia.
Neural Plast. 2012;2012:874387. doi: 10.1155/2012/874387. Epub 2012 Jun 27.
Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases.
亨廷顿病（HD）是一种神经退行性疾病，由亨廷顿蛋白中串联重复扩展编码多聚谷氨酰胺链引起。HD 涉及进行性精神、认知和运动症状，其选择性发病机制仍有待在机制上阐明。有一系列不同的大脑区域，包括大脑皮层和纹状体，已知在 HD 中受到影响，近年来积累了关于海马功能障碍的证据。在这篇综述中，我们将重点关注海马异常，特别是成年神经发生的缺陷。我们将讨论介导海马神经发生中断的潜在分子机制，以及这种细胞可塑性的缺陷如何反过来导致 HD 中突出的特定认知和情感症状。HD 的转基因动物模型的产生极大地促进了我们对分子、细胞和系统水平疾病机制的理解。转基因 HD 小鼠被发现表现出进行性行为改变，包括情感、认知和运动异常。在多种转基因 HD 小鼠系中发现，成年海马神经发生和突触可塑性被破坏，这可能有助于解释认知和情感功能障碍的特定方面。此外，这些小鼠模型为成年神经发生缺陷的潜在分子介质提供了深入了解，例如，5-羟色胺能和神经营养因子信号的中断。最后，已知许多能够增强成年海马神经发生的环境和药理学干预措施在小鼠模型中具有有益的情感和认知作用，这表明存在共同的分子靶点，可能对 HD 和相关疾病具有治疗用途。
