Activity-dependent synaptic plasticity expressed by NMDARs

描述(申请人提供)：中枢神经系统的兴奋性突触传递在很大程度上是由离子型谷氨酸受体的AMPA和NMDA亚型(分别为AMPAR和NMDAR)介导的。由于AMPAR介导了大部分谷氨酸能突触传递，兴奋性效应通常与AMPAR介导的突触反应的大小有关。众所周知，突触后NMDAR对AMPAR介导的信息传递具有多种形式的依赖活动的可塑性(如长时程增强和长时程抑制)，但NMDAR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NMDAR定位到突触前隔区，在那里它们被突触释放的谷氨酸激活，从而调节神经递质的释放。此外，越来越多的证据表明，NMDAR本身也受到动态调节，并受到依赖活动的长期可塑性的影响。然而，许多NMDAR可塑性的机制却知之甚少。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的神经元中进行的。因此，类似的机制在多大程度上适用于体内情况仍在很大程度上不得而知。此外，对NMDAR可塑性的诱导和表达机制知之甚少。在这项提议中，我们将试图通过分析两个表达强大NMDAR可塑性的关键海马区突触来填补这一知识空白。最重要的假设是，共同的机制是跨突触动态调节NMDAR的基础。我们将结合多种实验手段，如急性海马脑片电生理学、光遗传学、免疫电子显微镜、钙成像、体内基因敲除策略和转基因小鼠，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是否是短期和长期突触可塑性的调节者，以及NMDAR可塑性是否受到发育调节。NMDAR的调节失调与一系列神经精神疾病有关，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大脑功能的确切贡献，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的见解。

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.