Activity-Dependent Synaptic Plasticity Expressed by NMDA Receptors

描述(申请人提供)：由谷氨酸和电压激活的独特离子通道，NMDAR(NMDAR)在突触形成、突触可塑性、学习和记忆中发挥关键作用。NMDAR与精神分裂症、癫痫、帕金森病、药物成瘾和缺血/中风等多种神经系统疾病的发病或损害有关。细胞内信号通路对NMDARs的调控是一个活跃的研究领域。越来越多的证据现在表明，活动可以动态地调节NMDAR，尽管仍有许多未被探索。我们目前只知道NMDAR在少数突触上的活性依赖调节，尽管其潜在的分子机制和功能后果尚不清楚。我们建议从我们实验室最近发现的一种新形式开始，通过实验来确定活动依赖的NMDAR调节的机制和特定的功能贡献。最近我们发现，短暂的强直活动可以诱导NMDAR介导的海马苔藓纤维-CA3锥体细胞突触(NMDAR-mfLTP)传递的长期增强。初步数据表明，NMDAR-mfLTP在突触后以钙依赖的方式诱导和表达，并仅限于NMDAR。我们建议通过电生理记录和功能分析、药物操作和钙离子成像来研究NMDAR-mfLTP在急性海马片上的分子机制和功能后果。在诱导机制的研究中，我们将使用信号转导通路的抑制剂和激活剂，包括那些已知调节表达系统和培养神经元中NMDARs的信号转导通路的抑制剂和激活剂。我们将调查这种增强是否表现为NMDAR数量和/或功能的增加。在功能后果方面，我们将确定NMDAR-mfLTP是否与Mf-CA3突触钙信号的长期增强有关，并将检验NMDAR-mfLTP将显著改变该突触的输入/输出功能的假设。此外，我们将测试NMDAR-mfLTP一旦建立，是否可能改变兴奋性和抑制性CA3突触随后的可修饰性，这一现象被称为化塑性。最后，我们将在这个突触上寻找其他形式的NMDAR可塑性，包括长期抑制、去增强和去抑制。NMDARs的动态长期修饰可能会对正常和病理生理学产生重要影响。因此，了解这些形式的可塑性在细胞和网络水平上的作用对于更真实地描述大脑功能至关重要，并可能有助于开发治疗策略来逆转或防止NMDAR介导的调节失调或损伤。与公共健康相关：NMDA受体是大脑中参与兴奋性神经传递的受体的一个亚型，对突触形成、突触可塑性以及学习和记忆至关重要。神经元活动对NMDA受体的动态长期修饰可能会对正常和病理生理学产生重要影响，可能涉及缺血/中风、癫痫、精神分裂症、药物成瘾、慢性疼痛和帕金森病。了解这些受体是如何调节的，对于更真实地反映大脑功能至关重要，并可能有助于制定治疗策略，以逆转或防止NMDAR介导的调节失调或脑损伤。

DESCRIPTION (provided by applicant): Unique ion channels activated by both glutamate and voltage, NMDA receptors (NMDARs) play crucial roles in synapse formation, synaptic plasticity, learning, and memory. NMDARs have been associated with either the pathogenesis or the damage caused by several neurological disorders including schizophrenia, epilepsy, Parkinson's disease, drug addiction, and ischemia/stroke. The modulation of NMDARs by intracellular signaling pathways is an active area of investigation. Growing evidence now suggests that activity can dynamically regulate NMDARs, though much remains unexplored. We are currently aware of activity-dependent NMDAR regulation at only a few synapses, although its underlying molecular mechanisms and functional consequences remain unknown. We propose experiments to identify the mechanisms and specific functional contributions of activity-dependent NMDAR modulation, beginning with a novel form recently discovered in our laboratory. Recently we found that brief tetanic activity can induce long-term potentiation of NMDAR-mediated transmission at the hippocampal mossy fiber-CA3 pyramidal cell synapse (NMDAR-mfLTP). Preliminary data suggests that NMDAR-mfLTP is induced and expressed postsynaptically in a Ca2+-dependent process and is restricted to NMDARs. We propose to investigate the molecular mechanisms and functional consequences of NMDAR-mfLTP using electrophysiological recording and functional analysis, pharmacological manipulation, and Ca2+ imaging in acute hippocampal slices. In studies of the induction mechanism, we will use inhibitors and activators of signal transduction pathways including those known to regulate NMDARs in expression systems and cultured neurons. We will investigate whether this potentiation is expressed as an increase in NMDAR number and/or function. In terms of function consequences, we will determine whether NMDAR-mfLTP is associated with long-term enhancement of Ca2+ signaling at mf-CA3 synapses, and we will test the hypothesis that NMDAR-mfLTP will substantially modify the input/output function of this synapse. In addition, we will test whether NMDAR-mfLTP, once established, might modify the subsequent modifiability of excitatory and inhibitory CA3 synapses, a phenomenon known as metaplasticity. Finally, we will look for other forms of NMDAR plasticity at this synapse, including long-term depression, de-potentiation, and de-depression. Dynamic long-term modification of NMDARs may have important consequences for both normal and pathological physiology. For this reason, understanding the role of these forms of plasticity at the cellular and network level is critical to a more realistic representation of brain function, and may contribute to the development of therapeutic strategies to reverse or prevent NMDAR-mediated dysregulation or damage. PUBLIC HEALTH RELEVANCE: NMDA receptors are a subtype of receptors in the brain that participate in excitatory neurotransmission and are crucial for synapse formation, synaptic plasticity and learning and memory. Dynamic long-term modification of NMDA receptors by neuronal activity may have important consequences for both normal and pathological physiology with potential involvement in ischemia/stroke, epilepsy, schizophrenia, drug addiction, chronic pain, and Parkinson's disease. Understanding how these receptors are regulated is critical to a more realistic representation of brain function, and may contribute to the development of therapeutic strategies to reverse or prevent NMDAR-mediated dysregulation or brain damage.