A role for EphB and NMDARs in dendritic spine formation

EphB 和 NMDAR 在树突棘形成中的作用

• 批准号: 7233124
• 负责人: MATTHEW S KAYSER
• 金额: $ 2.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233124
• 关键词: Address; Animals; Binding; Brain; Cells; Chromosome Pairing; Complex; Cultured Cells; Cytoskeletal Proteins; Dendrites; Dendritic Spines; Development; Disease; Eph Family Receptors; EphA1 Receptor; Ephrin B Receptor; Ephrins; Excitatory Synapse; Fragile X Syndrome; Hippocampus (Brain); Human; Human Pathology; Image; Knock-out; Knockout Mice; Lasers; Life; Ligands; Mental Retardation; Microscopy; Molecular; Morphogenesis; Morphology; N-Methyl-D-Aspartate Receptors; Neurologic; Neurons; Pharmacology; Phenotype; Process; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recruitment Activity; Regulation; Rett Syndrome; Role; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; System; Testing; Time; Vertebral column; Week; Work; density; extracellular; insight; postsynaptic; presynaptic; receptor; receptor binding; receptor function; research study; synaptic function; synaptogenesis; two-photon

DESCRIPTION (provided by applicant): The majority of mature excitatory synapses in the CNS occur on specialized morphologic structures known as dendritic spines, and it is clear from studies in cell culture that the EphB receptor tyrosine kinase and the NMDAR are involved in proper spine and synapse formation. Recent work has also shown that activated EphB can both recruit and modulate the function of NMDARs. Aim 1 of this proposal will determine the steps of dendritic spine morphogenesis that are regulated by EphB receptor signaling by examining and manipulating neurons over time from EphB null mice. Aim 2 will assess the ability of activated EphB to recruit NMDARs in a more complex system, cortical slice culture, using fluorescently-tagged receptors and two-photon microscopy. Finally, the known interaction of EphB and NMDARs suggests a coordinated role during the development of dendritic spines; Aim 3 will directly test for this cooperative activity in cortical slice using pharmacology to manipulate receptor function and two-photon imaging to visualize spine morphology. Increased understanding of these molecular mechanisms is critical in addressing human neurologic diseases whose phenotype include abnormal spine formation, such as Fragile X, Down, and Rett Syndromes.

描述（由申请人提供）： 中枢神经系统中的大多数成熟兴奋性突触发生在被称为树突状棘的专用形态结构上，并且从细胞培养的研究中可以清楚地看出，EPHB受体酪氨酸激酶和NMDAR与适当的脊柱和突触形成有关。最近的工作还表明，活化的EPHB既可以募集并调节NMDAR的功能。该提案的目标1将确定树突状脊柱形态发生的步骤，这些步骤通过EPHB受体信号传导调节，通过检查和操纵EPHB无效小鼠的神经元。 AIM 2将使用荧光标记的受体和两光子显微镜评估活化的EPHB在更复杂的皮质切片培养中募集NMDAR的能力。最后，EPHB和NMDAR的已知相互作用表明在树突棘的发展中具有协调的作用。 AIM 3将使用药理学直接测试皮质切片中的这种合作活动，以操纵受体功能和两光子成像，以可视化脊柱形态。对这些分子机制的了解对解决人类神经系统疾病至关重要，其表型包括异常的脊柱形成，例如脆弱的X，Down和Rett综合征。