Exploring the contribution of astrocytes to Huntington disease

项目摘要 亨廷顿病(HD)是一种致命性、进行性的成人常染色体显性遗传性神经退行性疾病 临床上以认知、精神和运动障碍为特征。中纹状体棘变性 神经元(MSN)是HD最显著的神经病理改变。目前，还没有 HD的神经保护治疗和对症治疗也大多无效。突变的 亨廷顿蛋白(MHTT)广泛表达于神经细胞和非神经细胞中，但意义重大 神经变性只在大脑中的一小部分神经元中观察到。了解产生的毒性 通过mHTT在给定的细胞类型中，HD中的细胞相互作用和潜在的分子变化 对于经典的行为缺陷和选择性退行性疾病来说，很可能是设计有效的关键 治疗这种疾病的方法。 这项建议的目标之一是扩大我们对全长mHTT(fl-mhtt)贡献的认识。 纹状体MSN中星形胶质细胞表达缺失。星形胶质细胞对于正常的功能和 神经系统的发育。它们调节突触活动和神经传递。我们有 在条件性FL-mHTT BACHD小鼠中表达星形胶质细胞对行为学有贡献 HD的神经病理表型。 BACHD小鼠的电生理研究显示，对MSN的抑制输入增加，并 减少这些神经元的紧张性抑制。纹状体生长抑素的自发放电增加 下丘脑纹状体内的GABA能中间神经元。我们发现细胞外GABA(e[GABA])在 12月龄BACHD小鼠的纹状体，随着mHTT在星形胶质细胞中表达的减少而减少。我们 还发现GABA转运体GAT1和GAT3的减少，这两个转运体负责摄取 E[GABA]，在12月龄BACHD小鼠纹状体。 最近的研究表明，星形胶质细胞对GABA能生长抑素中间神经元的激活有反应 通过GAT3，增强其对下游锥体神经元的抑制活性。我们 假设mHTT在生长抑素中间神经元和星形胶质细胞中引起的缺陷相互作用 增强对MSN的GABA能抑制活性。我们设计了实验来评估 MHTT表达的星形胶质细胞在MSN抑制增强和紧张性传导降低中的作用。 此外，我们将首次评估fl-mhtt在表达生长抑素中间神经元中的作用。 中棘神经元和类HD神经元在电生理变化中的作用 BACHD小鼠的表型。我们还将评估GABA转运体的过度表达在 纹状体可减少BACHD小鼠MSN的电生理缺陷和e[GABA]。

Project Summary Huntington's disease (HD) is a fatal, progressive adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits. Degeneration of striatum medium spiny neurons (MSN) is the most prominent neuropathological change observed in HD. At present, there are no neuroprotective treatments for HD and symptomatic treatments are also largely ineffective. The mutated huntingtin (mHTT) protein is widely expressed in neuronal and non-neuronal cells, yet significant neurodegeneration is only observed for a subset of neurons in the brain. Understanding the toxicity produced by mHTT in a given cell type, the cellular interactions and underlying molecular changes in HD that contribute to the classic behavioral deficits and selective degeneration are likely to be critical in the design of effective therapies for the disease. One goal of this proposal is to expand our knowledge of the contribution of full length-mHTT (fl-mHTT) expressing astrocytes to deficits in striatal MSNs. Astrocytes are critical to the proper function and development of the nervous system. They modulate synaptic activity and neurotransmission. We have demonstrated that fl-mHTT expressing astrocytes in conditional fl-mHTT BACHD mice contribute to behavioral and neuropathological phenotypes observed in HD. Electrophysiological studies in BACHD mice revealed increased inhibitory input onto MSNs and a reduction of tonic inhibition in these neurons. There is increased spontaneous firing of striatal somatostatin GABAergic interneurons in the BACHD striatum. We found increased extracellular GABA (e[GABA]) in the striatum of 12 month old BACHD mice that is reduced with a decrease of mHTT expression in astrocytes. We also identified a decrease in GABA transporters, GAT1 and GAT3, which are responsible for uptake of e[GABA], in the striatum of the 12 month old BACHD mice. Recent studies revealed that astrocytes respond to activation of GABAergic somatostatin interneurons in the cortex through GAT3 and increases their inhibitory activity onto downstream pyramidal neurons. We hypothesize that deficits elicited by mHTT in somatostatin interneurons and astrocytes interact to contribute to the increased GABAergic inhibitory activity onto MSNs. We have designed experiments to assess the contribution of mHTT expressing astrocytes to the increased inhibition and reduced tonic conduction of MSNs. Furthermore, we will provide the first assessment of the role fl-mHTT expressing somatostatin interneurons play in the development of the electrophysiological changes in medium spiny neurons and the HD-like phenotypes in the BACHD mice. We will also assess whether overexpression of GABA transporters in the striatum decreases the electrophysiological deficits and e[GABA] observed in MSNs in the BACHD mice.