NEUROBIOLOGY

神经生物学

• 批准号: 6108512
• 负责人: MICHAEL Van Doren JOHNSTON
• 金额: $ 34.46万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6108512
• 关键词: Rett syndrome; acetylcholine; autoradiography; axon; basal ganglia; cerebrospinal fluid; excitatory aminoacid; female; frontal lobe /cortex; gamma aminobutyrate; glutamate receptor; glutamates; high performance liquid chromatography; histology; human tissue; immunocytochemistry; kainate; laboratory mouse; neurotransmitter metabolism; pathologic process; postmortem; somesthetic sensory cortex; synapses; transcription factor; western blottings

Project 2, entitled "the Neurobiology of Rett Syndrome" focuses on the pathogenesis of the neuronal abnormalities in the brains of girls with Rett Syndrome (RS) utilizing postmortem tissue and a neonatal mouse preparation with cerebral cortical changes that resemble those in RS. Study of both the postmortem tissue and the mouse model in the same project is synergistic because the mouse model can be controlled and manipulated in ways that are impossible with postmortem tissue, and our work over the last period of support has uncovered striking parallels between the two. The project is divided into two subprojects, Project 2a is primarily concerned with changes in selected neurotransmitter synaptic markers and Project 2b focuses on cytoskeletal changes, especially in the dendritic marker microtubule associated protein. The specific aims of proposed autoradiographic, Western Blot and immunocytochemical experiments in Project 2a will test the hypothesis that: I. Disorders of cholinergic, glutamatergic and other neurotransmitter synapses play a fundamental role in the pathogenesis of RS. In human postmortem tissues, the abnormalities will be most dynamic in early infancy and childhood cases. II. Early molecular events after cholinergic denervation in cerebral cortex contribute to the elevations in GluRs observed in the youngest cases of RS, and possibly for other abnormalities in synapse-related proteins including glutamate transporters. Cortical cholinergic denervation will be modeled by neonatal nucleus basalis lesions in mice. III. Neonatal nucleus basalis lesions plus elevated extracellular glutamate induced by administering ammonium acetate will produce encephalopathy, seizures, and histologic changes that strongly resemble RS. IV. Enhancing cholinergic neurotransmission, either by increasing acetylcholine levels or enhancing the regrowth of nucleus basalis neurons, in the neonatal period may reverse cortical pathology in the models. We focus on the neurobiology of RS in brain tissue both to understand basic mechanisms and to design rational therapy.

项目2题为“Rett综合征的神经生物学”， 女孩脑神经元异常的发病机制 Rett综合征（RS）利用死后组织和新生小鼠 制备与RS相似的大脑皮质变化。 死后组织和小鼠模型的研究 该项目是协同的，因为小鼠模型可以控制， 以死后组织不可能的方式操纵， 在过去的支持期间， 两人之间该项目分为两个分项目，项目2a 主要涉及选定的神经递质突触的变化， 标记物和项目2b侧重于细胞骨架的变化，特别是在 树突标记微管相关蛋白。的具体目标 建议放射自显影、Western Blot和免疫细胞化学实验 在项目2a中将检验假设：I.胆碱能障碍， 突触和其他神经递质突触起着重要的作用 RS的发病机制。在人类死后的组织中， 在婴儿早期和儿童时期最为活跃。二.早期 大脑皮层胆碱能神经损伤后的分子事件 有助于在最年轻的病例中观察到的GluRs升高， RS，并可能为其他异常的突触相关蛋白 包括谷氨酸转运蛋白。去皮质胆碱能神经 通过小鼠中的新生基底核损伤来建模。三.新生核 基底病变加上细胞外谷氨酸升高诱导的 施用乙酸铵会产生脑病、癫痫发作， 组织学变化与RS非常相似。四.增强胆碱能 神经传递，无论是通过增加乙酰胆碱水平或增强 新生期基底核神经元的再生可能 逆转模型中的皮质病理学。我们专注于神经生物学 RS在脑组织中的应用，以了解基本机制和设计 理性治疗