Huntington's Disease Research Forum, Department of Life Sciences, The Open University, Milton Keynes, UK.
Neurodegener Dis. 2011;8(4):230-9. doi: 10.1159/000322540. Epub 2011 Feb 1.
The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs.
We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD.
We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex.
We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D(1) dopamine receptor agonist (SKF38393).
In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction.
亨廷顿病（HD）基因检测的引入使人们能够在明显的运动和认知症状出现之前，对人类基因携带者进行神经精神和认知特征分析。这些研究揭示了工作记忆和执行功能的早期下降、脑电图改变和纹状体多巴胺受体的丧失。工作记忆在前额叶皮层中进行处理，并受到外在多巴胺能输入的调节。
我们试图研究 HD 小鼠模型中内侧前额叶皮层的兴奋性突触功能和可塑性。
我们使用了 2 种 HD 小鼠模型，携带 89 和 116 个 CAG 重复（分别对应于临床前和症状状态），并在内侧前额叶皮层的冠状切片上进行了电生理场记录。
我们报告说，短期突触可塑性和长时程增强（LTP）受损，并且损伤的严重程度与 CAG 重复的大小相关。值得注意的是，在 D1 多巴胺受体激动剂（SKF38393）存在的情况下，LTP 和短期可塑性的缺陷得到了逆转。
在之前的一项研究中，我们证明了边缘回皮质中长时程抑郁（LTD）的缺陷也可以被多巴胺激动剂逆转。这些和我们当前的数据表明，皮质突触功能的多巴胺能调节不足是 HD 的早期事件，并且可能为减轻认知功能障碍提供一种途径。
