NR2B-dependent synaptic plasticity

NR2B 依赖性突触可塑性

• 批准号: 6908282
• 负责人: Mark R. Plummer
• 金额: $ 22.16万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908282
• 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）：神经系统发育中的一个关键事件是正确突触连接的形成，这是一个由内在细胞引导线索和从环境获得的外在“活动依赖”信息控制的过程。外部刺激在神经细胞之间的连接具有高度可塑性且容易被修改的关键时期产生最大的影响。在分子水平上，活性依赖性的两个关键调节因子是谷氨酸受体的 NMDA 亚型和脑源性神经营养因子 (BDNF)。通过使用选择性拮抗剂，每种拮抗剂都可以独立影响生长的神经纤维竞争突触后目标的能力，甚至影响发育过程中关键时期的持续时间。该提案的中心目标是阐明这两个分子之间的相互作用，从而深入了解它们如何协同工作以细化成年早期的突触连接。为了完成这项任务，我们将在我的实验室之前的工作基础上进行研究，表明 BDNF 可以修改海马神经元中 NMDA 受体的活性，特别是含有 NR2B 亚基的神经元。 NR2B 的表达水平与关键期持续时间高度相关，并且可能在个体发育过程中的突触可塑性中发挥重要作用。因此，我们将确定 BDNF 对 NMDA 受体的调节在早期发育过程中是否显着，它是否针对突触或突触外含有 NR2B 的 NMDA 受体，以及它是否是海马特异性的或也存在于其他大脑区域。我们还将利用我们的新发现，即 BNDF 对 NMDA 受体的调节是活性依赖性的，这是参与突触竞争的基本要求。我们将利用这些信息来确定 BDNF 调节是否是突触特异性的或细胞特异性的，是否涉及 BDNF 的神经元释放，以及是否像许多形式的突触可塑性一样，由通过 NMDA 受体的钙流入触发。增加我们对神经回路在发育过程中如何构建的了解，甚至可能帮助我们确定如何在脑外伤后重建这些通路。