Mechanisms and machinery mediating AMPA receptor anchoring in synaptic plasticity

大脑是由被称为神经元的神经细胞组成的，这些神经细胞通过称为突触的特定细胞连接进行通信。突触是细胞间的小连接，神经元之间的信息在这里被传输和存储(即作为记忆)。突触的信息存储被认为是通过突触效力(突触可塑性)的变化来调节的，这涉及到突触后位置蛋白质分布的动态变化。突触之间的信号传递是通过从突触前位置的上游神经元释放神经递质化学物质到下游受体细胞的突触后而启动的。哺乳动物大脑中的一种主要神经递质是氨基酸谷氨酸，它激活突触后的受体蛋白质分子，称为“受体”。该应用的核心谷氨酸受体是AMPA受体(AMPA-R)。AMPA-Rs通过结合谷氨酸使突触后膜去极化，从而启动神经传递。去极化是由谷氨酸引发的正电荷粒子(阳离子)通过AMPA-R流入突触后神经元而产生的电信号(去极化)。突触增强是信息存储的底物，是由于额外的AMPA-R被招募到突触后导致阳离子内流增加和去极化。增强的传递还需要AMPA-R在突触上的集中或聚集，以及它们相对于谷氨酸释放位点的保留。在这项建议中，我们将研究突触中AMPA-R动力学的机制，突触可塑性(因此，“学习”)。我们将使用高分辨率成像和功能方法来分析突触对增强刺激的反应中AMPA-R的聚集和保留。这些将提供突触可塑性背后的AMPA-Rs动力学的详细快照。我们有初步证据表明，AMPA-R的远端部分，即N-末端结构域(或NTD)，调节着受体在突触后位置的扩散/保留和聚集。因此，NTD似乎在AMPA-R介导的突触增强中扮演着目前难以捉摸的角色，因此在突触学习中也是如此。AMPA-R的保留也稳定了突触后结构，我们的数据表明NTD在这一过程中发挥了作用。由于突触消除是神经退行性病变的标志，NTD介导的受体保留将有可能对抗阿尔茨海默病和相关痴呆等神经疾病。这些观察，加上我们为NTD作为新的药物靶点积累的证据，突出了AMPA-R NTD在突触功能中的关键作用。总之，我们提出的工作将为AMPAR在突触学习和突触稳定中的作用提供机械性信息。

The brain is made up of nerve cells termed 'neurons', which communicate via specific cell junctions, called synapses. Synapses are small inter-cellular junctions where information between neurons is transmitted and stored (i.e. laid down as memories). Information storage at synapses is believed to be be mediated by changes in synapse efficacy (synaptic plasticity), which involves dynamic changes of protein distribution at the post-synaptic site.Signaling across synapses is initiated by the release of neurotransmitter chemicals from an 'upstream' neuron at the pre-synaptic site, onto the post-synapse of a downstream recipient cell. A primary neurotransmitter in the mammalian brain is the amino acid glutamate, which activates recipient protein molecules on the post-synapse, called 'receptors'. The glutamate receptor central to the application is the AMPA-receptor (AMPA-R). AMPA-Rs depolarize the post-synaptic membrane in response to binding glutamate and thereby initiate neurotransmission. Depolarization results from a glutamate-triggered influx of positively charged particles (cations), through the AMPA-R, into the post-synaptic neuron resulting in an electrical signal (depolarization). Synaptic potentiation, the substrate for information storage, results from the recruitment of additional AMPA-Rs to the postsynapse resulting in increased cation-influx and more depolarization. Potentiated transmission also requires the concentration or clustering of AMPA-Rs at the synapse and their retention opposite glutamate-release sites.In this proposal we will investigate mechanisms underlying AMPA-R dynamics at synapses that underlie synaptic plasticity (and thus 'learning'). We will assay the clustering and retention of AMPA-Rs at synapses in response to potentiating stimuli using high-resolution imaging and functional approaches. These will provide a detailed-snapshot of the AMPA-Rs dynamics underlying synaptic plasticity. We have preliminary evidence suggesting that the distal portion of the AMPA-R, the N-terminal domain (or NTD) regulates receptor diffusion/retention and clustering at post-synaptic sites. Hence, the NTD appears to play a currently elusive role in AMPA-R-mediated synapse potentiation and therefore in synaptic learning. AMPA-R retention also stabilizes post-synaptic structures, and our data point to a role for the NTD in this process. Since synapse elimination is a hallmark of neurodegneration, NTD-mediated receptor retention would have the potential to oppose neurological disorders such as Alzheimer's disease and related dementias. These observations, together with our accumulating evidence for the NTD as novel drug target, highlight a key role for the AMPA-R NTD in synapse function. In summary, our proposed work will provide mechanistic information into the role of AMPARs in synaptic learning and synapse stabilization.