Exploring the contribution of astrocytes to Huntington disease

探索星形胶质细胞对亨廷顿病的贡献

• 批准号: 10231078
• 负责人: Michelle Gray
• 金额: $ 44.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10231078
• 关键词: Adult; Affect; Astrocytes; Behavior; Behavioral; Brain; Cells; Clinical; Cognitive; Corpus striatum structure; D Cells; Data; Development; Disease; Disease Progression; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Feedback; Frequencies; Functional disorder; GABA Transporter 1; GABA transporter; GAT3 transporter; Genetic study; Glial Fibrillary Acidic Protein; Glutamates; Goals; Hippocampus (Brain); Huntington Disease; Huntington gene; Huntington protein; Interneurons; Knowledge; Length; Modeling; Molecular; Movement; Mus; Mutate; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Parvalbumins; Pathway interactions; Patients; Phenotype; Play; Proteins; Risk; Role; Signal Transduction; Somatostatin; Synapses; Thalamic structure; Toxic effect; Viral; base; behavioral phenotyping; cell type; clinical Diagnosis; design; effective therapy; experimental study; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; inhibitory neuron; motor deficit; mutant; nervous system development; neurotransmission; optogenetics; overexpression; symptom treatment; uptake

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. In protein extracted from the striatum of the 12 month old BACHD mice, we identified a decrease in GABA transporter 1, GAT1. The GAT1 transporter is responsible for uptake of e[GABA]. 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.

项目摘要 亨廷顿氏病（HD）是一种致命的，进行性的成人常染色体显性神经退行性疾病 以认知，精神病和运动缺陷为特征。纹状体中刺的变性 神经元（MSN）是HD中观察到的最突出的神经病理学变化。目前，没有 HD和症状治疗的神经保护治疗也很大程度上无效。突变 Huntingtin（MHTT）蛋白在神经元和非神经元细胞中广泛表达，但显着 仅观察到大脑中神经元子集的神经变性。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基础分子变化有助于 对于经典的行为缺陷和选择性变性，对于有效的设计可能至关重要 该疾病的疗法。 该建议的目标之一是扩大我们对全长MHTT（FL-MHTT）贡献的了解 表达星形胶质细胞对纹状体MSN的缺陷。星形胶质细胞对于适当的功能至关重要 神经系统的发展。它们调节突触活动和神经传递。我们有 证明有条件的FL-MHTT BACHD小鼠中表达星形胶质细胞的FL-MHTT有助于行为 和在HD中观察到的神经病理表型。 在Bachd小鼠中的电生理研究表明，对MSN和A的抑制性输入增加了 这些神经元中补品抑制的减少。纹状体生长抑素的自发性发射增加 Bachd纹状体中的GABA能中间神经元。我们发现增加了细胞外GABA（E [GABA]） 12个月大的BACHD小鼠的纹状体减少了星形胶质细胞中MHTT表达的降低。在 从12个月大的Bachd小鼠的纹状体中提取的蛋白质，我们确定了GABA的降低 转运蛋白1，GAT1。 GAT1转运蛋白负责摄取E [GABA]。 最近的研究表明，星形胶质细胞对GABA能生长抑制素中间神经元的激活有何反应 在皮质中，通过GAT3并增加了其在下游锥体神经元上的抑制活性。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 GABA能抑制活性增加了MSN。我们设计了实验来评估 MHTT表达星形胶质细胞对MSN的抑制增加和减少的补品传导的贡献。 此外，我们将对表达生长抑素中间神经元的角色进行首次评估 发挥中刺神经元和类似HD的电生理变化的发展 Bachd小鼠中的表型。我们还将评估GABA转运蛋白的过表达 纹状体减少了在BACHD小鼠中MSN中观察到的电生理缺陷和E [GABA]。