Exploring the contribution of astrocytes to Huntington disease
Exploring the contribution of astrocytes to Huntington disease
批准号:
10663211
负责人:
Michelle Gray
金额:
$44.27万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
未结题
起止时间:
2015-08-01 至 2025-06-30
关键词:
AdultAffectAstrocytesBehaviorBehavioralBrainCellsClinicalCognitiveCorpus striatum structureD CellsDataDevelopmentDiseaseDisease ProgressionDopamine D1 ReceptorDopamine D2 ReceptorElectrophysiology (science)Experimental DesignsFeedbackFrequenciesFunctional disorderGABA Transporter 1GAT3 transporterGenetic studyGlial Fibrillary Acidic ProteinGlutamatesGoalsHippocampusHuntington DiseaseHuntington geneInterneuronsKnowledgeLengthModelingMolecularMovementMusMutateNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsParvalbuminsPathway interactionsPatientsPhenotypePlayProteinsRiskRoleSignal TransductionSomatostatinSynapsesThalamic structureToxic effectViralautosomebehavioral phenotypingcell typeclinical diagnosisdesigneffective therapyexperimental studyextracellularhippocampal pyramidal neuroninhibitory neuronmotor deficitmutantnervous system developmentneuropathologyneuroprotectionneurotransmissionoptogeneticsoverexpressionsymptom treatmentuptake
中文摘要
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中观察到的最显著的神经病理学变化。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。在
从12个月大的BACHD小鼠的纹状体中提取的蛋白质,我们鉴定出GABA减少,
转运蛋白1 GAT 1 GAT 1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,
在中棘神经元和HD样神经元电生理变化的发展中起作用
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]。
英文摘要
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. 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.
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科研奖励(0)
会议论文
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项目类别:
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资助金额:$33.41万
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财政年份:2019
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负责人:Michelle Gray
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依托单位:
Exploring the contribution of astrocytes to Huntington disease
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Exploring the contribution of astrocytes to Huntington disease
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财政年份:2010
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批准号:7871941
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资助金额:$17.48万
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The Role of Astrocytes in Huntington's Disease
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The Role of Astrocytes in Huntington's Disease
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批准号:8247166
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资助金额:$17.48万
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财政年份:2010
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负责人:Michelle Gray
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The Role of Astrocytes in Huntington's Disease
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批准号:8048109
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资助金额:$17.48万
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财政年份:2010
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负责人:Michelle Gray
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依托单位:
Mauthner Cell Development in the Zebrafish Mutant
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批准号:6557537
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项目类别:
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资助金额:$2.37万
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财政年份:2001
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负责人:Michelle Gray
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依托单位:
Mauthner Cell Development in the Zebrafish Mutant
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批准号:6316935
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资助金额:$2.38万
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财政年份:2001
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依托单位:
海外基金