Molecular organization of CNS synapses

中枢神经系统突触的分子组织

基本信息

批准号：
7482443
负责人：
MORGAN H. SHENG
金额：
$ 21.5万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7482443
关键词：
Affinity Chromatography Binding Biochemical Biological Brain Cells Chromosome Pairing Classification Complex Coupled Coupling DLG4 gene Development Disease Family Family member Grant Hippocampus (Brain)Immunoblotting Immunoprecipitation Lead Learning Long-Term Depression Long-Term Potentiation MAPK14 gene MAPK8 gene Mediating Memory Mink Mitogen-Activated Protein Kinases Modification Molecular Molecular Genetics Monomeric GTP-Binding Proteins N-Methyl-D-Aspartate Receptors NMDA receptor antagonist NR2B NMDA receptor Neurologic Neurons Neurosciences Protein Kinase Protein Overexpression Proteins Proteomics RNA Interference Rattus Receptor Signaling Regulation Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Slice Synapses Synaptic Transmission Synaptic plasticity Testing discs, large (Drosophila) homolog 2 protein, rat excitatory neuron genetic regulatory protein insight member neuropsychiatry novel postsynaptic presynaptic density protein 95 receptor research study synaptic depression trafficking

项目摘要

DESCRIPTION (provided by applicant): Synaptic plasticity is essential for brain function and development. The overall objective of this proposal is to understand the molecular mechanisms by which activation of NMDA receptors (NMDARs) can lead to bidirectional modification of synaptic strength (LTP and LTD) in the hippocampus. Our Preliminary Studies suggest that NR2A- and NR2B-containing NMDARs are selectively coupled to LTP or LTD of hippocampal CA1 synapses, respectively. Our overall hypothesis, supported by preliminary experiments, is that NR2A and NR2B subunits are differentially associated with postsynaptic signaling molecules that mediate plasticity changes. These findings offer exciting new inroads into understanding NMDAR signaling, which is a central question in neuroscience and relevant to brain maturation, learning and memory, and many neurological and neuropsychiatric diseases. The Specific Aims of this grant will extend these observations and investigate the underlying mechanisms of NMDAR signaling in systematic fashion. Aim 1 will characterize the differential roles of NR2A- versus NR2B-NMDARs in Ras-MAP kinase signaling, AMPAR trafficking and hippocampal synaptic plasticity, using a combination of pharmacological and molecular genetic approaches. Aim 2 will test the idea that different members of the PSD-95 family of scaffold proteins (which bind to NR2A/2B) have different functions in AMPAR trafficking, synaptic transmission and LTP/LTD. Aim 3 will use immunoprecipitation of NMDAR complexes from brain to identify and subsequently characterize the specific signaling proteins that are preferentially associated with NR2A- versus NR2B-NMDARs. Finally, Aim 4 will identify and characterize the effector proteins of the small GTPase Rap, which is emerging as an important player in synaptic depression and possibly synapse elimination. Together these aims will allow us to gain novel and fundamental insight into the molecular organization of NMDARs and their postsynaptic signaling pathways in central excitatory neurons.

描述（由申请人提供）：突触可塑性对于大脑功能和发育至关重要。该建议的总体目的是了解NMDA受体（NMDAR）激活的分子机制可以导致海马中突触强度（LTP和LTD）的双向修饰。我们的初步研究表明，含NR2A和NR2B的NMDAR分别与海马CA1突触的LTP或LTD有选择性耦合。我们的总体假设得到了初步实验的支持，是NR2A和NR2B亚基与介导可塑性变化的突触后信号分子有不同的相关性。这些发现为理解NMDAR信号传导提供了令人兴奋的新侵害，这是神经科学中的一个核心问题，与大脑成熟，学习和记忆以及许多神经和神经精神疾病有关。该赠款的具体目的将扩展这些观察结果，并以系统的方式研究NMDAR信号的潜在机制。 AIM 1将使用药理和分子遗传学方法的组合来表征NR2A-与NR2B-NMDAR在RAS-MAP激酶信号，AMPAR运输和海马突触可塑性中的差异作用。 AIM 2将测试以下观点：PSD-95支架蛋白家族的不同成员（与NR2A/2B结合）在AMPAR运输，突触传播和LTP/LTD中具有不同的功能。 AIM 3将使用来自大脑的NMDAR复合物的免疫沉淀来识别并随后表征与NR2A-与NR2B-NMDAR相关的特定信号蛋白。最后，AIM 4将识别并表征小GTPase RAP的效应蛋白，该蛋白质正在成为突触抑郁症和可能消除突触的重要参与者。这些目标共同使我们能够对中央兴奋性神经元中NMDAR的分子组织及其突触后信号通路获得新颖和基本的见解。