Ephrin-A3 in Neuron-Glia Communication

Ephrin-A3 在神经元-胶质细胞通讯中的作用

• 批准号: 7185423
• 负责人: William B. Stallcup
• 金额: $ 38.34万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185423
• 关键词: Affect; Astrocytes; Autistic Disorder; Axon; Brain; CSPG4 gene; Cell physiology; Chromosome Pairing; Communication; Dendrites; Dendritic Spines; Development; Disease model; Eph Family Receptors; EphA1 Receptor; EphA4 Receptor; Ephrin-A3; Ephrins; Epilepsy; Functional disorder; Genes; Goals; Head; Heparitin Sulfate; Hippocampus (Brain); Knockout Mice; Learning; Ligands; Link; Mediating; Memory; Mental Retardation; Mutation; NG2 antigen; Neck; Nervous system structure; Neuroglia; Neurons; Numbers; Peripheral Nervous System; Physiology; Play; Property; Receptor Protein-Tyrosine Kinases; Regulation; Research; Role; Series; Shapes; Signal Pathway; Signal Transduction; Structure; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Vertebral column; hippocampal pyramidal neuron; long term memory; nervous system disorder; prevent; size; synaptogenesis; tool

Glial cells play a key role in neuronal development and function. However, the signals exchanged by glial cells and neurons are poorly understood. Increasing evidence supports the notion that ephrins and Eph receptors play an important role in the interactions between glial cells and neuronal axons as well as dendrites in different parts of the central and peripheral nervous system. We recently discovered a new form of neuron-glia communication that involves the ephrin-A3 ligand expressed on the surface of astrocytes in the hippocampus and the EphA4 receptor tyrosine kinase expressed on dendritic spines. Dendritic spines are small protrusions on neuronal dendrites that make synaptic contact with axonal terminals. Typically, mature spines have an enlarged head connected to the dendrite through a narrow neck. Changes in the shape, size and number of dendritic spines in the hippocampus likely contribute to learning and storing longterm memories. Our evidence suggests that the interplay between ephrin-A3 and EphA4 mediates a form of repulsive communication between astrocytes and neurons that counteracts signals promoting the enlargement of spines and prevents distortion and disorganization of the spines. This may represent a mechanism regulating spine remodeling during learning and memory formation. Importantly the communication likely is bidirectional, with ephrin-A3 also initiating signals that affect the properties of astrocytes coming in contact with EphA4-positive dendrites. The goal of this project is to evaluate the role of glial ephrin-A3 in the regulation of dendritic spine development and remodeling and synaptic transmission in hippocampal neurons. Furthermore, we will investigate the signaling pathways mediated by ephrin-A3 and their role in astrocyte physiology. Recently obtained ephrin-A3 knockout mice will be important tools to achieve these goals. The proposed research will provide information on whether mutations in the ephrin-A3 gene contribute to neurological diseases characterized by abnormalities in dendritic spines¿including mental retardation, autism, epilepsy, and schizophrenia¿and whether the ephrin-A3 knockout mouse may represent a useful neurological disease model. Strategies to manipulate ephrin function in glial cells could help treatment of neurological disorders involving aberrant neuron-glia interactions in the hippocampus and other regions of the nervous system.

神经胶质细胞在神经元发育和功能中起着关键作用。然而，神经胶质细胞交换的信号 对细胞和神经元的了解很少。越来越多的证据支持这样的观点， 受体在神经胶质细胞和神经元轴突之间的相互作用中起重要作用， 中枢和周围神经系统不同部位的树突。我们最近发现了一种 神经元-神经胶质细胞通讯，涉及ephrin-A3配体在星形胶质细胞表面表达， 海马和树突棘上表达的EphA 4受体酪氨酸激酶。树突棘 是神经元树突上的小突起，与轴突末梢进行突触接触。典型地， 成熟的刺有一个扩大的头部，通过一个狭窄的颈部与树突相连。变化 海马体中树突棘的形状、大小和数量可能有助于长期的学习和储存。 回忆我们的证据表明肝配蛋白-A3和EphA 4之间的相互作用介导了一种形式的免疫抑制。 星形胶质细胞和神经元之间的排斥性通讯， 扩大脊柱，并防止脊柱扭曲和解体。这可能代表了一种 在学习和记忆形成过程中调节脊柱重塑的机制。重要的是 通信可能是双向的，肝配蛋白A3也启动影响细胞特性的信号。 星形胶质细胞与EphA 4阳性树突接触。该项目的目标是评估 神经胶质细胞ephrin-A3在树突棘发育、重塑和突触传递中的调节作用 海马神经元此外，我们将研究ephrin-A3介导的信号通路， 它们在星形胶质细胞生理学中的作用最近获得的ephrin-A3基因敲除小鼠将是重要的工具， 以实现这些目标。这项拟议的研究将提供有关肝配蛋白A3突变是否 基因导致神经系统疾病，其特征是树突棘异常，包括 精神发育迟缓、自闭症、癫痫和精神分裂症？以及肝配蛋白A3敲除小鼠是否可能 代表了一种有用的神经疾病模型。操纵神经胶质细胞中ephrin功能的策略可能 帮助治疗涉及海马中异常神经元-神经胶质相互作用的神经系统疾病， 神经系统的其他区域。