Pathophysiology of Transgenic Mouse Models of Huntington's Disease

描述(申请人提供)：亨廷顿病(HD)的致命突变是亨廷顿蛋白内的一种扩展的三核苷酸(CAG)重复，最终导致选择性神经变性，特别是在纹状体和皮质内。这项建议研究了HD潜在的功能改变的细胞机制。新出现的证据表明，纹状体和皮质神经元和回路的功能障碍发生在疾病表型的发展过程中，远在出现显著的细胞丢失之前。纹状体的形态变化最初可能是纹状体中型棘神经元(MSSN)固有功能特性的改变，但最终需要皮质纹状体谷氨酸能输入的异常才能表达表型。皮质纹状体通路的故障是复杂的，并且有多种变化，与疾病状态的显着年龄相关的一过性和更慢性的相互作用证明了这一点。也有越来越多的证据表明，皮质微循环的变化相互作用，导致皮质纹状体通路功能障碍。关于细胞和回路改变的时间序列，以及纹状体和皮质中选择性神经元脆弱性的原因，人们知之甚少。我们将使用转基因小鼠来解决这些重要问题。这项建议将研究发生的功能相互作用，使特定的神经元群体更容易受到功能障碍和随后的HD变性的影响。我们假设，HD中最明显的导致功能障碍和病理的细胞变化是细胞-细胞相互作用的结果，而不仅仅是细胞-自主变化的结果。我们将在三个特定目标上验证我们的假设：1.确定使纹状体投射神经元和中间神经元亚群在功能障碍和变性中具有不同易感性的电生理特性；2.检测HD模型小鼠大脑皮层兴奋和抑制平衡的变化，促进和使纹状体异常；3.检查突变型Huntingtin的广泛表达是否必要，以在已确定的MSSN群体中产生不同的电生理变化。这些研究将为HD的合理治疗提供新的基础，为药物干预提供更多的限制性靶点，也将对了解其他CAG三联体重复疾病和神经退行性疾病具有重要意义。

DESCRIPTION (provided by applicant): The lethal mutation in Huntington's disease (HD) is an expanded trinucleotide (CAG) repeat within the huntingtin protein which ultimately causes selective neurodegeneration especially within the striatum and cortex. This proposal examines cellular mechanisms underlying functional alterations in HD. Emerging evidence indicates that dysfunctions of striatal and cortical neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium- sized spiny neurons (MSSNs), but ultimately require abnormalities in the corticostriatal glutamatergic inputs for the phenotype to be expressed. Malfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. Little is known about the temporal sequence of cellular and circuit alterations, as well as the causes of selective neuronal vulnerability in striatum and cortex. We will use genetically-modified mice to address these important questions. This proposal will examine the functional interactions that occur to make specific neuronal populations more vulnerable to dysfunction and subsequent degeneration in HD. We hypothesize that the most conspicuous cellular alterations leading to dysfunction and pathology in HD result from a combination of cell-cell interactions and are not solely the outcome of cell- autonomous changes. We will test our hypothesis in three specific aims designed to: 1. Determine the electrophysiological properties that make subpopulations of striatal projection neurons and interneurons differentially vulnerable to dysfunction and degeneration in mouse models of HD, 2. Examine the alterations in the balance of excitation and inhibition in the cerebral cortex of mouse models of HD that facilitate and enable abnormalities in the striatum and 3. Examine if widespread expression of mutant huntingtin is necessary to produce differential electrophysiological alterations in identified populations of MSSNs. These studies will provide the basis for novel rational treatments of HD by delineating more restricted targets for drug intervention and also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.