PRESYNAPTIC NEUROCHEMICAL MARKERS

突触前神经化学标志物

基本信息

批准号：
6267438
负责人：
KIRK A. FREY
金额：
$ 18.57万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 1999-05-31
项目状态：
已结题

项目摘要

The experiments proposed in this project will elucidate important relationships between ligand binding site markers of cholinergic or dopaminergic neurons and the integrity and density of their terminals in the brain. We will seek to distinguish those markers that respond dynamically to perturbations in synaptic activity from markers whose expression appears related only to the survival of intact presynaptic nerve endings. The former may be of utility in elucidating regulatory responses to disease or following treatment, but will not serve as reliable quantitative markers of neuronal density. Markers satisfying the latter criterion are well-suited to the prospective analysis of disease and therapeutic interventions in neurodegenerative disorders, potentially providing objective measures of progression or response. The capability to determine such markers in noninvasive clinical settings, with the use of emission tomographic imaging, may ultimately permit detailed analyses of neuronal survival and death not previously possible. Our hypotheses are focused on the study of radioligand binding sites located on the membranes of synaptic vesicles, specific to cholinergic or to monoaminergic neurons. The ligands [3H]vesamicol and [3H]methoxytetrabenazine will be applied to the evaluation of these neuronal populations, respectively. We will compare the neurobiologic expression and regulation of these binding sites with additional measures of cell membrane transport sites for the presynaptic uptake of choline or of dopamine. Regulatory changes in the activities of these latter sites are well-known in the case of cholinergic neurons, and are potentially present in dopaminergic nerve terminals as well. Our experimental design will involve the use of chronic drug administration in animals to produce alterations in synaptic activity by potentiating or inhibiting neurotransmission. Under these conditions, regulatory modulation in neurotransmitter numbers are known to occur, permitting parallel documentation of the altered state of synaptic activity. We will then determine the possible presence of changes in the synaptic vesicle and presynaptic membrane uptake sites. Comparison of the above results of drug challenges and those following selective brain lesions, resulting in cortical cholinergic deficits or in striatal dopaminergic deficits, will be make with ligand binding markers in postmortem brain samples from subjects with Alzheimers's and Parkinson's diseases. Combined, these results will enhance understanding of the relateive contributions of neuronal loss and of secondary regulatory responses in these idiopathic disorders. Future clinical research studies, based on carefully-chosen markers of synaptic integrity, will then be possible.

该项目中提出的实验将阐明配体结合位点标记之间的重要关系胆碱能或多巴胺能神经元的完整性和大脑中终端的密度。我们将寻求区分那些动态响应的标记突触活动中的扰动来自标记的标记表达出现仅与完整的生存有关突触前神经结尾。前者可能是有效的阐明对疾病或以下疾病的调节反应处理，但不会用作可靠的定量神经元密度的标记。满足后者的标记标准非常适合前瞻性分析神经退行性的疾病和治疗干预措施疾病，有可能提供客观的措施进展或响应。确定这样的能力使用非侵入性临床环境中的标记排放层析成像，最终可能允许神经元生存和死亡的详细分析以前可能。我们的假设集中于放射性的研究位于突触的膜上的结合位点囊泡，特定于胆碱能或单胺能神经元。配体[3H] vesamicol和 [3H]甲氧基苯甲嗪将应用于评估这些神经元种群分别。我们将比较神经生物学表达和调节这些结合位点具有其他细胞的测量突触前吸收的膜运输地点胆碱或多巴胺。监管变化这些后者的活动在此情况下是众所周知的胆碱能神经元，有可能存在于多巴胺能神经终末。我们的实验设计将涉及使用慢性药物管理在动物中，通过增强或抑制神经传递。在这些条件，神经递质的调节调节已知数字发生，允许并行突触活动状态改变状态的文档。然后，我们将确定可能存在变化突触囊泡和突触前膜摄取部位。比较上述毒品挑战结果和那些遵循选择性脑损伤的人，导致皮质胆碱能缺陷或纹状体多巴胺能缺陷，将使用配体结合标记在来自阿尔茨海默氏症受试者的验尸大脑样本和帕金森氏病。结合了这些结果增强对相关贡献的理解神经元丧失和继发性调节反应这些特发性疾病。未来的临床研究研究，基于精心选择的突触标记诚信将是可能的。