NEUROBIOLOGY

神经生物学

• 批准号: 6347584
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347584
• 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”，重点关注