Activity-Dependent Synaptic Plasticity Expressed by NMDA Receptors

描述（由申请人提供）：由谷氨酸和电压激活的独特离子通道，NMDA受体（NMDAR）在突触形成、突触可塑性、学习和记忆中起关键作用。NMDAR与几种神经系统疾病（包括精神分裂症、癫痫、帕金森病、药物成瘾和缺血/中风）的发病机制或损伤相关。通过细胞内信号传导途径调节NMDAR是一个活跃的研究领域。现在越来越多的证据表明，活动可以动态调节NMDAR，尽管还有很多尚未探索。我们目前只知道在少数突触的活动依赖性NMDAR调节，但其潜在的分子机制和功能后果仍然未知。我们提出实验，以确定活动依赖性NMDAR调制的机制和具体的功能贡献，从我们实验室最近发现的新形式开始。最近，我们发现短暂的强直活动可以诱导海马苔藓纤维-CA 3锥体细胞突触（NMDAR-mfLTP）NMDAR介导的传递的长时程增强。初步数据表明，NMDAR-mfLTP的诱导和表达突触后的钙离子依赖性的过程中，并限于NMDAR。我们建议在急性海马脑片中使用电生理记录和功能分析、药理学操作和Ca 2+成像来研究NMDAR-mfLTP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途径的抑制剂和激活剂，包括那些已知在表达系统和培养的神经元中调节NMDAR的抑制剂和激活剂。我们将研究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-CA 3突触处的Ca 2+信号的长期增强相关，并且我们将测试NMDAR-mfLTP将实质上修改该突触的输入/输出功能的假设。此外，我们将测试是否NMDAR-mfLTP，一旦建立，可能会修改兴奋性和抑制性CA 3突触，称为metaplasticity现象的后续可修改性。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。NMDAR的动态长期修饰可能对正常和病理生理学都具有重要影响。出于这个原因，理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表示脑功能至关重要，并且可能有助于开发逆转或预防NMDAR介导的失调或损伤的治疗策略。公共卫生相关性：NMDA受体是大脑中参与兴奋性神经传递的受体亚型，对突触形成、突触可塑性以及学习和记忆至关重要。NMDA受体通过神经元活性的动态长期修饰可能对正常和病理生理学具有重要影响，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是至关重要的，以更现实的表现脑功能，并可能有助于发展的治疗策略，以扭转或防止NMDAR介导的失调或脑损伤。

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.