Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
基本信息
- 批准号:10840162
- 负责人:
- 金额:$ 7.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAstrocytesBehavioralBrainClinicalCognitiveCorpus striatum structureDevelopmentDiseaseElectrophysiology (science)Experimental DesignsGoalsHuntington DiseaseHuntington geneInterneuronsKnowledgeLengthMolecularMusMutateNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsPatientsPhenotypePlayRiskRoleSomatostatinSynapsesToxic effectautosomecell typeclinical diagnosisdesigneffective therapyextracellularhippocampal pyramidal neuronmotor deficitnervous system developmentneuropathologyneuroprotectionneurotransmissionoverexpressionsymptom treatmentuptake
项目摘要
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.
项目摘要
亨廷顿病(Huntington 'sDisease,HD)是一种致死性、进行性的成人常染色体显性遗传性神经退行性疾病
临床上表现为认知、精神和运动缺陷。纹状体中棘变性
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的神经保护治疗和对症治疗也基本无效。突变的
亨廷顿蛋白(mHTT)在神经元和非神经元细胞中广泛表达,但其在神经元和非神经元细胞中具有显著的生物学活性。
仅在脑中的一部分神经元中观察到神经变性。了解所产生的毒性
通过mHTT在给定的细胞类型,细胞相互作用和潜在的分子变化,在HD,有助于
经典的行为缺陷和选择性变性可能是设计有效的
治疗这种疾病。
该建议的一个目标是扩大我们对全长-mHTT(fl-mHTT)贡献的认识
表达星形胶质细胞以减少纹状体MSN中的缺陷。星形胶质细胞对正常功能至关重要,
神经系统的发育。它们调节突触活动和神经传递。我们有
结果表明,条件fl-mHTT BACHD小鼠中表达fl-mHTT的星形胶质细胞有助于行为
和HD中观察到的神经病理表型。
BACHD小鼠的电生理学研究显示,MSNs的抑制性输入增加,
这些神经元的紧张性抑制减少。纹状体生长抑素自发放电增加
BACHD纹状体中的GABA能中间神经元。我们发现,增加细胞外GABA(e[GABA])在
在12个月大的BACHD小鼠的纹状体中,随着星形胶质细胞中mHTT表达的减少而减少。我们
还确定了GABA转运蛋白GAT 1和GAT 3的减少,GAT 1和GAT 3负责摄取
e[GABA],在12月龄BACHD小鼠的纹状体中。
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GAT 3在皮质中的作用,并增加其对下游锥体神经元的抑制活性。我们
假设mHTT引起生长抑素中间神经元和星形胶质细胞相互作用,
对MSN的GABA能抑制活性增加。我们设计了实验来评估
表达mHTT的星形胶质细胞对MSN的抑制增加和紧张性传导减少的贡献。
此外,我们将提供fl-mHTT表达生长抑素中间神经元的作用的第一个评估,
在中型棘神经元和HD样神经元电生理变化的发展中发挥作用
BACHD小鼠中的表型。我们还将评估GABA转运蛋白在脑组织中的过度表达,
纹状体减少BACHD小鼠MSN中观察到的电生理缺陷和e[GABA]。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Progressive cardiac arrhythmias and ECG abnormalities in the Huntington's disease BACHD mouse model.
亨廷顿病 BACHD 小鼠模型中进行性心律失常和心电图异常。
- DOI:10.1093/hmg/ddz295
- 发表时间:2020
- 期刊:
- 影响因子:3.5
- 作者:Zhu,Yujie;Shamblin,Isaac;Rodriguez,Efrain;Salzer,GraceE;Araysi,Lita;Margolies,KatherineA;Halade,GaneshV;Litovsky,SilvioH;Pogwizd,Steven;Gray,Michelle;Huke,Sabine
- 通讯作者:Huke,Sabine
Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice.
不间断的CAG重复驱动纹状体选择性转录病和人类亨廷顿蛋白BAC小鼠的核发病机理。
- DOI:10.1016/j.neuron.2022.01.006
- 发表时间:2022-04-06
- 期刊:
- 影响因子:16.2
- 作者:Gu, Xiaofeng;Richman, Jeffrey;Langfelder, Peter;Wang, Nan;Zhang, Shasha;Banez-Coronel, Monica;Wang, Huei-Bin;Yang, Lucia;Ramanathan, Lalini;Deng, Linna;Park, Chang Sin;Choi, Christopher R.;Cantle, Jeffrey P.;Gao, Fuying;Gray, Michelle;Coppola, Giovanni;Bates, Gillian P.;Ranum, Laura P. W.;Horvath, Steve;Colwell, Christopher S.;Yang, X. William
- 通讯作者:Yang, X. William
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Michelle Gray其他文献
Michelle Gray的其他文献
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{{ truncateString('Michelle Gray', 18)}}的其他基金
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 - 财政年份:2015
- 资助金额:
$ 7.16万 - 项目类别:
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:
10437708 - 财政年份:2015
- 资助金额:
$ 7.16万 - 项目类别:
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:
10663211 - 财政年份:2015
- 资助金额:
$ 7.16万 - 项目类别:
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:
9324375 - 财政年份:2015
- 资助金额:
$ 7.16万 - 项目类别:
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:
9757818 - 财政年份:2015
- 资助金额:
$ 7.16万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
8456153 - 财政年份:2010
- 资助金额:
$ 7.16万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
7871941 - 财政年份:2010
- 资助金额:
$ 7.16万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
8642674 - 财政年份:2010
- 资助金额:
$ 7.16万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
8247166 - 财政年份:2010
- 资助金额:
$ 7.16万 - 项目类别:
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