Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK.
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK; School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0SP, UK.
Neurobiol Dis. 2014 Jun;66:19-27. doi: 10.1016/j.nbd.2014.02.004. Epub 2014 Feb 19.
Huntington's disease (HD) is an inherited neurodegenerative disorder that is classically defined by a triad of movement and cognitive and psychiatric abnormalities with a well-established pathology that affects the dopaminergic systems of the brain. This has classically been described in terms of an early loss of dopamine D2 receptors (D2R), although interestingly the treatments most effectively used to treat patients with HD block these same receptors. We therefore sought to examine the dopaminergic system in HD not only in terms of striatal function but also at extrastriatal sites especially the hippocampus, given that transgenic (Tg) mice also exhibit deficits in hippocampal-dependent cognitive tests and a reduction in adult hippocampal neurogenesis. We showed that there was an early reduction of D2R in both the striatum and dentate gyrus (DG) of the hippocampus in the R6/1 transgenic HD mouse ahead of any overt motor signs and before striatal neuronal loss. Despite downregulation of D2Rs in these sites, further reduction of the dopaminergic input to these sites by either medial forebrain bundle lesions or receptor blockade using sulpiride was able to improve both deficits in motor performance and adult hippocampal neurogenesis. In contrast, a reduction in dopaminergic innervation of the neurogenic niches resulted in impaired neurogenesis in healthy WT mice. This study therefore provides evidence that D2R blockade improves hippocampal and striatal deficits in HD mice although the underlying mechanism for this is unclear, and suggests that agents working within this network may have greater effects than previously thought.
亨廷顿病（HD）是一种遗传性神经退行性疾病，其经典特征是运动、认知和精神异常三联征，并有明确的病理学影响大脑中的多巴胺能系统。这在经典上被描述为多巴胺 D2 受体（D2R）的早期丧失，尽管有趣的是，用于治疗 HD 患者最有效的治疗方法会阻断这些相同的受体。因此，我们不仅试图研究 HD 中的多巴胺能系统在纹状体功能方面，还试图研究纹状体以外的部位，特别是海马体，因为转基因（Tg）小鼠也表现出海马体依赖的认知测试缺陷和成年海马神经发生减少。我们发现，在 R6/1 转基因 HD 小鼠出现明显运动迹象之前，在纹状体神经元丧失之前，纹状体和海马体齿状回（DG）中的 D2R 就已经早期减少。尽管这些部位的 D2R 下调，但通过内侧前脑束损伤或使用舒必利阻断受体进一步减少这些部位的多巴胺能输入，能够改善运动表现和成年海马神经发生的缺陷。相比之下，减少神经发生龛的多巴胺能神经支配会导致健康 WT 小鼠的神经发生受损。因此，这项研究提供了证据表明 D2R 阻断可改善 HD 小鼠的海马体和纹状体缺陷，尽管其潜在机制尚不清楚，并表明在该网络中起作用的药物可能比以前认为的更有效。
