Effects of glutamate uptake on the neuropathophysiology of Huntintgton's disease

谷氨酸摄取对亨廷顿病神经病理生理学的影响

• 批准号: 7615307
• 负责人: Benjamin R Miller
• 金额: $ 2.8万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-02 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615307
• 关键词: Affect; Amino Acids; Animals; Antioxidants; Ascorbic Acid; Attenuated; Autopsy; Behavior; Behavioral; Ceftriaxone; Cells; Cessation of life; Code; Corpus striatum structure; Coupled; Disease; Disease model; Electrophysiology (science); Exhibits; Extracellular Fluid; Frequencies; Genes; Glutamate Transporter; Glutamates; Goals; Huntington Disease; Impaired cognition; In Vitro; Inherited; Link; Mediating; Modeling; Monitor; Monobactams; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Output; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Property; Public Health; Regulation; Reporting; Research; Risk; Role; Scanning; Shapes; Signal Transduction; Synapses; Synaptic Transmission; Testing; Tissues; United States; Up-Regulation; Vitamins; Wild Type Mouse; ascorbate; base; disease phenotype; extracellular; information processing; motor control; mouse model; neurochemistry; neuropathology; neurophysiology; oxidative damage; uptake

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a dominantly inherited, incurable neurodegenerative disease affecting primarily the striatum and corticostriatal pathway. Although the ultimate fate of HD is selective neurodegeneration in striatum and cortex, emerging evidence suggests that dysregulated information processing in the corticostriatal circuit, rather than death alone, underlies HD neuropathophysiology. In striatum, for example, dysregulated corticostriatal-dependent glutamatergic signaling and alterations in the neurochemical milieu result in a host of abnormal striatal firing patterns long before cell loss. Consistent with this view is the fact that GLT1, which is the primary glutamate (GLU) transporter responsible for regulating synaptic levels of GLU, is dysfunctional in striatum of HD mouse models. As a result, the level of striatal ascorbate (vitamin C; AA), which is an antioxidant vitamin directly linked to the degree of GLU uptake and corticostriatal excitability, is markedly decreased in these models. Uptake of GLU and AA release, moreover, modulate excitability of striatum by shaping the firing patterns of striatal neurons. Because proper levels of both GLU uptake and AA in striatum are necessary for behavioral output, these mechanisms likely play key roles in HD neuropathology. Interestingly, the ?-lactam antibiotic ceftriaxone upregulates the functional expression of GLT1 and attenuates multiple signs of the HD behavioral phenotype in the R6/2 mouse, which is the most characterized HD model. Therefore, the overall goal of the proposed research is to characterize the effects of a ceftriaxone-mediated increase in GLU uptake via GLT1 on the neurophysiology of HD. We hypothesize that ceftriaxone will normalize the altered activity patterns of striatal neurons and reverse deficient striatal AA in the R6/2 mouse. We will test our hypothesis with two parallel approaches. In one we will use electrophysiology to record activity of striatal neurons in freely behaving R6/2 mice and wild-type littermate controls treated with either ceftriaxone or vehicle. We will record spike activity of single-units and local field potentials of neuronal ensembles to investigate the role of GLU uptake on behaviorally relevant striatal activity. In separate, but similarly treated animals, we will use voltammetry coupled with cortical stimulation to monitor the effects of glutamate uptake on corticostriatal-dependent release of AA in striatum of R6/2 mice. These studies will provide the basis for evaluating ceftriaxone as a potential therapy for HD. Unfortunately, there are currently no effective cures or treatments for HD. Because HD affects ~30,000 people in the United States and ~150,000 more are at risk for inheriting the gene, further research on HD has significant public health implications.

描述（由申请人提供）：亨廷顿病（HD）是一种显性遗传性、不可治愈的神经退行性疾病，主要影响纹状体和皮质纹状体通路。虽然HD的最终命运是纹状体和皮质的选择性神经变性，但新出现的证据表明，皮质纹状体回路中的信息处理失调，而不仅仅是死亡，是HD神经病理生理学的基础。例如，在纹状体中，皮质纹状体依赖性神经元能信号的失调和神经化学环境的改变导致了早在细胞损失之前的一系列异常纹状体放电模式。与此观点一致的是，GLT 1是负责调节GLU突触水平的主要谷氨酸（GLU）转运蛋白，在HD小鼠模型的纹状体中功能障碍。结果，纹状体抗坏血酸（维生素C; AA），这是一种抗氧化维生素直接链接到GLU摄取和皮质纹状体兴奋性的程度，在这些模型中的水平显着降低。此外，GLU的摄取和AA的释放通过塑造纹状体神经元的放电模式来调节纹状体的兴奋性。由于纹状体中适当水平的GLU吸收和AA对于行为输出是必要的，因此这些机制可能在HD神经病理学中发挥关键作用。有趣的是，？内酰胺抗生素头孢曲松在R6/2小鼠中上调GLT 1的功能性表达并减弱HD行为表型的多种迹象，R6/2小鼠是最具特征的HD模型。因此，拟定研究的总体目标是表征头孢曲松介导的GLU摄取增加（通过GLT 1）对HD神经生理学的影响。我们假设，头孢曲松将正常化纹状体神经元的活动模式的改变和逆转缺陷纹状体AA在R6/2小鼠。我们将用两种平行的方法来检验我们的假设。在一个实验中，我们将使用电生理学来记录自由行为的R6/2小鼠和用头孢曲松或载体处理的野生型同窝对照小鼠的纹状体神经元的活性。我们将记录单个单位的尖峰活动和神经元集合的局部场电位，以研究GLU摄取对行为相关纹状体活动的作用。在单独的，但类似的治疗动物，我们将使用伏安法加上皮层刺激，以监测谷氨酸摄取的影响，对皮质纹状体依赖性释放AA的R6/2小鼠纹状体。这些研究将为评价头孢曲松作为HD的潜在治疗方法提供基础。 不幸的是，目前没有有效的治疗或治疗HD。由于HD影响美国约30，000人，约150，000人有遗传该基因的风险，因此对HD的进一步研究具有重大的公共卫生意义。

项目成果

Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction.

• DOI: 10.1016/j.neuroscience.2010.10.070
• 发表时间: 2011-02-03
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Wilber, A. A.;Walker, A. G.;Southwood, C. J.;Farrell, M. R.;Lin, G. L.;Rebec, G. V.;Wellman, C. L.
• 通讯作者: Wellman, C. L.