Mechanisms and machinery mediating AMPA receptor anchoring in synaptic plasticity

介导突触可塑性 AMPA 受体锚定的机制和机制

• 批准号: BB/T015993/1
• 负责人: Ingo Greger
• 金额: $ 55.04万
• 依托单位: MRC Laboratory of Molecular Biology
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT015993%2F1
• 关键词: Mechanisms; machinery; mediating; AMPA; receptor

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.

大脑由称为“神经元”的神经细胞组成，它们通过称为突触的特定细胞连接进行通信。突触是小的细胞间连接，神经元之间的信息在这里传输和存储（即作为记忆）。突触的信息储存被认为是由突触效能的变化（突触可塑性）介导的，这涉及突触后位点蛋白质分布的动态变化。突触间的信号传导是由突触前位点的“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谷氨酸，它激活突触后的受体蛋白分子，称为“受体”。对应用至关重要的谷氨酸受体是AMPA受体（AMPA-R）。AMPA-R响应于结合谷氨酸而使突触后膜去活化，从而启动神经传递。去极化由谷氨酸触发的带正电荷的粒子（阳离子）通过AMPA-R流入突触后神经元导致电信号（去极化）。突触增强是信息储存的底物，其产生于额外的AMPA-R向突触后的募集，导致阳离子流入增加和更多的去极化。增强的传递也需要AMPA-R在突触处的浓度或聚集以及它们在谷氨酸释放位点对面的保留。在这个提议中，我们将研究突触处AMPA-R动力学的潜在机制，这些机制是突触可塑性的基础（从而是“学习”）。我们将使用高分辨率成像和功能方法分析AMPA-R在突触处对增强刺激的响应的聚集和保留。这些将提供一个详细的快照AMPA-Rs动态突触可塑性的基础。我们有初步的证据表明，AMPA-R的远端部分，N-末端结构域（或NTD）调节受体的扩散/保留和聚集在突触后位点。因此，NTD似乎在AMPA-R介导的突触增强和突触学习中起着目前难以理解的作用。AMPA-R保留也稳定突触后结构，我们的数据指出NTD在这个过程中的作用。由于突触消除是神经退化的标志，NTD介导的受体保留将有可能对抗神经系统疾病，如阿尔茨海默病和相关痴呆症。这些观察结果，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，我们的工作将为AMPAR在突触学习和突触稳定中的作用提供机制信息。

项目成果

Allosteric coupling of sub-millisecond clamshell motions in ionotropic glutamate receptor ligand-binding domains.

• DOI: 10.1038/s42003-021-02605-0
• 发表时间: 2021-09-09
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Rajab S;Bismin L;Schwarze S;Pinggera A;Greger IH;Neuweiler H
• 通讯作者: Neuweiler H