NR2B-dependent synaptic plasticity

NR2B 依赖性突触可塑性

• 批准号: 7090618
• 负责人: Mark R. Plummer
• 金额: $ 21.64万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090618
• 关键词: NMDA receptors; biological signal transduction; brain derived neurotrophic factor; calcium flux; developmental neurobiology; electrophysiology; genetically modified animals; glutamates; hippocampus; immunofluorescence technique; intermolecular interaction; laboratory mouse; neural plasticity; neuroanatomy; neurogenesis; neurons; synaptic vesicles; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): A pivotal event in the developing nervous system is formation of proper synaptic connections, a process governed by intrinsic cellular guidance cues and by extrinsic, "activity-dependent", information obtained from the environment. External stimuli have their greatest impact during critical periods in which connections between nerve cells are highly plastic and susceptible to modification. At the molecular level, two of the key regulators of activity-dependence are the NMDA subtype of glutamate receptor, and brain-derived neurotrophic factor (BDNF). With the use of selective antagonists, each has been shown independently to affect the ability of growing nerve fibers to compete for postsynaptic targets and even influence the duration of critical periods during development. The central goal of this proposal is to elucidate interactions between these two molecules, thus providing insights into how they work together to refine synaptic connectivity into early adulthood.To accomplish this task, we will build upon previous work from my laboratory showing that BDNF can modify the activity of NMDA receptors in hippocampal neurons, particularly those containing the NR2B subunit. Expression levels of NR2B are highly correlated with critical period duration, and may play an obligatory role in synaptic plasticity during ontogeny. Therefore, we will determine whether BDNF modulation of NMDA receptors is prominent during early development, whether it targets synaptic or extrasynaptic NR2B-containing NMDA receptors, and whether it is hippocampus-specific or found in other brain regions as well. We will also capitalize on our new finding that modulation of NMDA receptors by BNDF is activity-dependent, an essential requirement for involvement in synaptic competition. We will use this information to determine whether BDNF modulation is synapse- or cell-specific, whether it involves neuronal release of BDNF, and whether, like many forms of synaptic plasticity, it is triggered by calcium influx through NMDA receptors.Addressing these questions will increase our knowledge of how neural circuits are constructed during development, and perhaps even help us determine how to rebuild these pathways after brain trauma.

描述（由申请人提供）：发育中神经系统中的关键事件是形成适当的突触连接，这是一个由固有的蜂窝引导线索控制的过程，以及从环境中获得的外在的“活动依赖性”的外部“活动依赖性”的过程。外部刺激在神经细胞之间的连接高度塑性且容易受到修饰的关键时期具有最大的影响。在分子水平上，活性依赖性的两个关键调节剂是谷氨酸受体的NMDA亚型和脑衍生的神经营养因子（BDNF）。通过使用选择性拮抗剂，每个人都被独立显示，以影响不断增长的神经纤维竞争突触后靶标的能力，甚至影响发育过程中关键时期的持续时间。该提案的核心目的是阐明这两个分子之间的相互作用，从而提供有关它们如何共同工作以将突触连通性完善到成年早期的见解。要完成这项任务，我们将基于我实验室的先前工作，表明BDNF可以修改NMDA受体在Hippocampal Neurons中的活动，尤其是那些含有NR2B的nm2b subtiTIT。 NR2B的表达水平与关键时期持续时间高度相关，并且在个体发育过程中可能在突触可塑性中起强制性作用。因此，我们将确定NMDA受体的BDNF调节在早期发育过程中是否突出，是针对含有突触的NR2B NMDA受体的靶向突触的还是含有海马的NMDA受体，还是在其他大脑区域中发现的。我们还将利用我们的新发现，即BNDF对NMDA受体的调节依赖于活动，这是参与突触竞争的必不可少的要求。我们将使用这些信息来确定BDNF调节是否是突触或细胞特异性的，它是否涉及BDNF的神经元释放，以及像多种形式的突触可塑性一样，它是由NMDA受体涌入钙涌入引发的。在这些问题上，这些问题会增加我们在开发过程中的神经环境的知识，甚至可以帮助我们在开发过程中的构建方式，并依次决定了这些问题的brain脑中，并且如何反复这些问题。

项目成果

Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.

• DOI: 10.1371/journal.pgen.1001331
• 发表时间: 2011-03
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Pramparo T;Libiger O;Jain S;Li H;Youn YH;Hirotsune S;Schork NJ;Wynshaw-Boris A
• 通讯作者: Wynshaw-Boris A