Activity-dependent synaptic plasticity expressed by NMDARs

描述（由申请人提供）：中枢神经系统的兴奋性突触传递主要由嗜离子性谷氨酸受体的AMPA和NMDA亚型（分别为AMPAR和NMDAR）介导。由于ampar介导了大部分谷氨酸能突触传递，兴奋效应通常与ampar介导的突触反应的大小有关。虽然众所周知，突触后NMDARs可以控制ampar介导的多种形式的活动依赖性可塑性（如长期增强和长期抑制），但NMDARs也可以促进突触的信息传递和神经元的兴奋性。此外，某些突触将NMDARs定位于突触前隔室，在那里它们被突触释放的谷氨酸激活可以调节神经递质释放。此外，越来越多的证据表明，NMDARs本身也受到动态调节，并受到活动依赖的长期可塑性的影响。然而，人们对NMDAR可塑性的许多机制知之甚少。到目前为止，大多数关于NMDAR调控的研究都是在表达系统和培养神经元中进行的。因此，类似的机制在多大程度上适用于体内情况仍然很大程度上是未知的。此外，对NMDAR可塑性的诱导和表达机制还缺乏了解。在本提案中，我们将通过分析表达NMDAR可塑性的两个关键海马突触来填补这一知识空白。最重要的假设是，NMDARs在突触间的动态调节背后有共同的机制。利用互补的实验方法，如急性海马切片电生理学、光遗传学、免疫电子显微镜、钙成像、体内敲低策略和转基因小鼠，我们将研究特定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NMDARs是否调节短期和长期突触可塑性，以及NMDAR可塑性是否受发育调节。NMDARs的失调与许多神经精神疾病有关，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这些受体对正常脑功能的精确贡献，并为开发在特定疾病状态下恢复受体功能的新策略提供重要见解。

DESCRIPTION (provided by applicant): 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.