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: 7097232
• 负责人: MATTHEW S KAYSER
• 金额: $ 2.97万
• 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/7097232
• 关键词: NMDA receptors; biological signal transduction; cerebral cortex; dendrites; ephrins; fluorescence microscopy; laboratory mouse; neurogenesis; predoctoral investigator; protein protein interaction; protein structure function; protein tyrosine kinase; receptor binding; receptor expression

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）： 中枢神经系统中大多数成熟的兴奋性突触发生在称为树突棘的特殊形态结构上，细胞培养研究清楚地表明，EphB 受体酪氨酸激酶和 NMDAR 参与适当的树突棘和突触形成。最近的研究还表明，激活的 EphB 可以招募和调节 NMDAR 的功能。该提案的目标 1 将通过检查和操纵 EphB 缺失小鼠的神经元随时间的变化来确定由 EphB 受体信号传导调节的树突棘形态发生的步骤。目标 2 将使用荧光标记受体和双光子显微镜，评估激活的 EphB 在更复杂的系统（皮质切片培养物）中招募 NMDAR 的能力。最后，已知的 EphB 和 NMDAR 相互作用表明在树突棘发育过程中发挥协调作用。目标 3 将使用药理学来操纵受体功能和双光子成像来可视化脊柱形态，直接测试皮质切片中的这种协作活动。增加对这些分子机制的了解对于解决人类神经系统疾病至关重要，这些疾病的表型包括脊柱形成异常，例如脆性 X 综合症、唐氏综合症和雷特综合症。