Activity-dependent synaptic plasticity expressed by NMDARs

中枢神经系统的兴奋性突触传递主要由AMPA和NMDA介导 离子型谷氨酸受体亚型（分别为AMPAR和NMDAR）。因为AMPAR介导 大部分的突触传递，兴奋性功效通常与 AMPAR介导的突触反应的大小。虽然突触后NMDAR是众所周知的 门控几种形式的活动依赖性可塑性（例如长时程增强和长时程抑制） 在AMPAR介导的传递中，NMDAR也有助于突触处的信息传递， 神经元兴奋性此外，某些突触将NMDAR定位于突触前区室 其中它们被突触释放的谷氨酸激活可以调节神经递质的释放。此外，委员会认为， 越来越多的证据表明，NMDAR本身也是动态调节的， to activity活动dependent依赖性long-term长期plasticity可塑性.然而，许多潜在的NMDAR可塑性机制是 不太了解。 到目前为止，大多数针对NMDAR调控的研究都是在表达系统中进行的， 培养的神经元因此，类似机制适用于体内情况的程度仍然存在 大部分未知。此外，缺乏知识存在的诱导和表达的机制， NMDAR可塑性。在本提案中，我们将试图通过分析两个关键问题来填补这一知识空白。 表达强大NMDAR可塑性的海马突触。总体假设是， NMDAR跨突触的动态调节机制。结合使用 互补的实验方法，如急性海马切片的电生理学， 光遗传学，免疫电镜，钙成像，体内敲除策略和转基因 小鼠，我们将研究特定的信号通路和受体亚基在NMDAR可塑性中的作用。 此外，我们将确定突触前NMDAR是否是短期和长期的调节器。 突触可塑性，以及NMDAR可塑性是否受到发育调节。 NMDAR的失调与广泛的神经精神疾病有关，例如 精神分裂症、癫痫、慢性疼痛、药物成瘾、阿尔茨海默病和亨廷顿病。 了解NMDAR可塑性的分子机制有助于阐明NMDAR的精确表达。 这些受体对正常大脑功能的贡献，也为发展中国家提供了重要的见解。 在特定疾病状态下恢复受体功能的新策略。

Excitatory synaptic transmission in the central nervous system is largely mediated by the AMPA and NMDA subtypes of ionotropic glutamate receptors (AMPAR and NMDAR, respectively). Because AMPARs mediate the bulk of glutamatergic synaptic transmission, excitatory efficacy is commonly associated with the magnitude of AMPAR-mediated synaptic responses. While postsynaptic NMDARs are well-known for gating several forms of activity-dependent plasticity (e.g. long-term potentiation and long-term depression) of AMPAR-mediated transmission, NMDARs can also contribute to information transfer at synapses and to neuronal excitability. In addition, certain synapses localize NMDARs to the presynaptic compartment where their activation by synaptically-released glutamate can regulate neurotransmitter release. Moreover, an expanding body of evidence indicates that NMDARs themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. However, many of the mechanisms underlying NMDAR plasticity are poorly understood. Thus far, most studies addressing NMDAR regulation have been performed in expression systems and cultured neurons. As a result, the extent to which similar mechanisms apply to the in vivo situation remains largely unknown. Furthermore, scant knowledge exists on the mechanisms of induction and expression of NMDAR plasticity. In this proposal, we will attempt to fill this knowledge gap by analyzing two key hippocampal synapses that express robust NMDAR plasticity. The overarching hypothesis is that common mechanisms underlie dynamic regulation of NMDARs across synapses. Using a combination of complementary experimental approaches, such as electrophysiology in acute hippocampal slices, optogenetics, immunoelectron microscopy, calcium imaging, in vivo knockdown strategies and transgenic mice, we will investigate the role of specific signaling pathways and receptor subunits in NMDAR plasticity. In addition, we will determine whether presynaptic NMDARs are regulators of short-term and long-term synaptic plasticity, and whether NMDAR plasticity is developmentally regulated. Dysregulation of NMDARs has been implicated in a wide range of neuropsychiatric disorders, such as schizophrenia, epilepsy, chronic pain, addiction to drugs, Alzheimer's disease, and Huntington's disease. Understanding the molecular mechanisms underlying NMDAR plasticity could help elucidate the precise contribution of these receptors to normal brain function, and also provide significant insights in developing novel strategies for restoring receptor function in specific disease states.