Receptors moving in and out of the synapse The number of neurotransmitter receptors and their spatial organization on the postsynaptic site is a central determinant of synaptic efficacy. Sophisticated techniques to visualize and track the movement of single molecules have provided us with profound new insights into these dynamics. We now know that neurotransmitter receptors undergo movements on different scales. Groc and Choquet review our present understanding of the mechanisms that regulate glutamate receptor localization and clustering. Receptor movements are fundamental to basic synaptic function and participate in many forms of synaptic plasticity. Science, this issue p. eaay4631 BACKGROUND Since it was established that the cognitive brain is formed mostly by an interconnected network of neurons that communicate at contact sites termed synapses, intense research has aimed at identifying their molecular composition and physiological roles. The discovery that the efficacy of synaptic transmission can be modified by neuronal activity has undoubtedly been a major step in understanding brain function. The various forms of activity-dependent synaptic plasticity were early on proposed to play central roles in brain adaptation, learning, and memory. This motivated neurophysiologists to understand the mechanisms of synaptic plasticity, initially within the sole framework of the quantal properties of transmitter release, largely ignoring the cell biology revolution that was occurring in parallel. In the 1970s, at the same time that synaptic plasticity was discovered, the fluidity of cell membranes was established. Surprisingly, these contemporary findings seldom crossed paths. As cell biologists established the major roles of receptor trafficking in cell function, neurophysiologists still largely viewed synapse function as based on unitary receptor properties and control of transmitter release. It has been only about 20 years since the two fields cross-fertilized and the regulation of receptor movements into and out of synapses emerged as a fundamental mechanism for synaptic plasticity. ADVANCES Largely based on the development of imaging approaches, including single-molecule tracking, receptors have been demonstrated to undergo a variety of movements, from long-range rapid motor-based intracellular transport, to short-range Brownian surface diffusion, and intercompartment exchange by membrane trafficking. For efficient synaptic transmission, receptors must accumulate in front of neurotransmitter release sites. This is accomplished through a set of interactions with intracellular scaffold proteins, transmembrane auxiliary subunits, or adhesion proteins and other extracellular elements. This duality of receptor movements and stabilization has led to the important concept that the number of functionally responsive receptors at synapses results from the interplay between reversible receptor stabilization and dynamic equilibrium between pools of receptors in the synaptic, extrasynaptic, and intracellular compartments. Coarse receptor distribution along dendrites is largely achieved by intracellular transport. Because exchange of receptors between surface and intracellular compartments seems to occur largely at extrasynaptic sites, reversible surface receptor diffusion trapping at synapses has emerged as a central mechanism to control their availability for synaptic activation. Receptor stabilization and movements are all profoundly regulated by short- and long-term neuronal activity patterns. Reciprocally, evidence has accumulated that receptor movements participate in many forms of synaptic plasticity. Notably, altered receptor movements are observed in many neurodevelopmental, psychiatric, or neurodegenerative pathological models as indicated in the figure [the + and – signs indicate the reported positive and negative modulation of the indicated trafficking and stabilization processes during either normal (blue) or pathological (red) synaptic function]. Whether altered receptor trafficking represents the primum movens of some neurological diseases remains to be established, but is certainly an attractive hypothesis. OUTLOOK Most receptor trafficking studies have been performed in reduced experimental systems such as neuronal cultures. This has limited our understanding of the physiological impact of these processes. The development of brighter and smaller probes together with new imaging modalities are on the verge of allowing routine measurement of receptor movements in more physiological settings such as brain slices and in vivo. There is little doubt that qualitatively comparable trafficking modalities will be identified. Reciprocally, tools are being developed to control the various types of receptor movements, from blocking surface diffusion by receptor cross-linking to stopping receptor exocytosis with light-activated toxins. Often, these trafficking tools do not impair basic synaptic function, because resilience of the synapse to trafficking alterations is high owing to the amount of available receptors, as well as the trapping capacities and nanoscale organization of the synapse. Combining measurement and control of receptor movements will not only allow better understanding of their contribution to synaptic and neuronal function but also provide valuable tools for identifying the role of synaptic plasticity in higher brain functions. Controlling receptor movements or stabilization may eventually represent an alternative therapeutic strategy to receptor activity modulation approaches in a variety of synaptic and network-based brain diseases. Neurotransmitter receptors undergo a variety of large- and small-scale movements. Movements of large amplitude constantly reshuffle the receptor distribution (e.g., surface diffusion and intracellular transport). Movements at interfaces (e.g., between synaptic and extrasynaptic sites, between intracellular and surface compartments) are of small amplitude but have huge functional impacts. Each of these movements is highly regulated and finely tuned in physiological and pathological conditions. Regulation of neurotransmitter receptor content at synapses is achieved through a dynamic equilibrium between biogenesis and degradation pathways, receptor stabilization at synaptic sites, and receptor trafficking in and out synapses. In the past 20 years, the movements of receptors to and from synapses have emerged as a series of highly regulated processes that mediate postsynaptic plasticity. Our understanding of the properties and roles of receptor movements has benefited from technological advances in receptor labeling and tracking capacities, as well as from new methods to interfere with their movements. Focusing on two key glutamatergic receptors, we review here our latest understanding of the characteristics of receptor movements and their role in tuning the efficacy of synaptic transmission in health and brain disease.

中文翻译：

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连接谷氨酸受体运动和突触功能

进出突触的受体神经递质受体的数量及其在突触后部位的空间组织是突触功效的主要决定因素。用于可视化和跟踪单个分子运动的复杂技术为我们提供了对这些动力学的深刻新见解。我们现在知道神经递质受体在不同尺度上进行运动。Groc 和 Choquet 回顾了我们目前对调节谷氨酸受体定位和聚类机制的理解。受体运动是基本突触功能的基础，并参与多种形式的突触可塑性。科学，这个问题 p。eaay4631 背景 由于已经确定认知大脑主要由在称为突触的接触部位进行通信的相互连接的神经元网络形成，因此大量研究旨在确定它们的分子组成和生理作用。突触传递的功效可以被神经元活动改变的发现无疑是理解大脑功能的重要一步。各种形式的活动依赖性突触可塑性很早就被提出在大脑适应、学习和记忆中发挥核心作用。这促使神经生理学家了解突触可塑性的机制，最初是在递质释放量子特性的唯一框架内，在很大程度上忽略了同时发生的细胞生物学革命。在 1970 年代，在发现突触可塑性的同时，也确立了细胞膜的流动性。令人惊讶的是，这些当代发现很少交叉。随着细胞生物学家确定受体运输在细胞功能中的主要作用，神经生理学家仍然在很大程度上将突触功能视为基于单一受体特性和对递质释放的控制。自从这两个领域交叉受精并且调节受体进出突触的运动成为突触可塑性的基本机制以来，仅仅过去了大约 20 年。进展主要基于成像方法的发展，包括单分子跟踪，受体已被证明可以进行各种运动，从基于运动的远程快速细胞内运输到短程布朗表面扩散，通过膜运输进行室间交换。为了有效的突触传递，受体必须在神经递质释放位点前积累。这是通过与细胞内支架蛋白、跨膜辅助亚基或粘附蛋白和其他细胞外元件的一系列相互作用来实现的。受体运动和稳定的这种二元性导致了一个重要的概念，即突触中功能响应受体的数量是可逆受体稳定与突触、突触外和细胞内受体库之间的动态平衡之间相互作用的结果。沿树突的粗受体分布主要是通过细胞内运输实现的。由于表面和细胞内隔室之间的受体交换似乎主要发生在突触外位点，因此突触处的可逆表面受体扩散捕获已成为控制突触激活可用性的中心机制。受体稳定和运动都受到短期和长期神经元活动模式的深刻调节。相反，越来越多的证据表明受体运动参与了多种形式的突触可塑性。值得注意的是，在许多神经发育、精神病、或如图所示的神经退行性病理模型 [+ 和 - 符号表示在正常（蓝色）或病理性（红色）突触功能期间所报告的指定运输和稳定过程的正负调节]。受体运输的改变是否代表了一些神经系统疾病的主要动力仍有待确定，但肯定是一个有吸引力的假设。展望 大多数受体贩运研究都是在减少的实验系统中进行的，例如神经元培养。这限制了我们对这些过程的生理影响的理解。更明亮和更小探针的开发以及新的成像方式即将允许在更多生理环境（如脑切片和体内）中对受体运动进行常规测量。毫无疑问，将确定质量上具有可比性的贩运方式。相反，正在开发工具来控制各种类型的受体运动，从通过受体交联阻止表面扩散到用光激活毒素阻止受体胞吐作用。通常，这些贩运工具不会损害基本的突触功能，因为由于可用受体的数量以及突触的捕获能力和纳米级组织，突触对贩运改变的弹性很高。结合受体运动的测量和控制不仅可以更好地理解它们对突触和神经元功能的贡献，而且还可以提供有价值的工具来确定突触可塑性在高级大脑功能中的作用。在各种突触和基于网络的脑疾病中，控制受体运动或稳定可能最终代表受体活性调节方法的替代治疗策略。神经递质受体经历各种大小不一的运动。大幅度的运动不断地重新调整受体分布（例如，表面扩散和细胞内运输）。界面（例如，突触和突触外位点之间，细胞内和表面隔间之间）的运动幅度很小，但具有巨大的功能影响。这些运动中的每一个都在生理和病理条件下受到高度调节和微调。突触中神经递质受体含量的调节是通过生物发生和降解途径之间的动态平衡来实现的，突触位点的受体稳定性，以及受体进出突触。在过去的 20 年里，受体进出突触的运动已经成为一系列高度调节的过程，介导突触后可塑性。我们对受体运动特性和作用的理解得益于受体标记和跟踪能力方面的技术进步，以及干扰其运动的新方法。重点关注两个关键的谷氨酸能受体，我们在此回顾了我们对受体运动特征及其在调节突触传递在健康和脑部疾病中的功效的作用的最新理解。受体进出突触的运动已经成为一系列高度调节的过程，介导突触后的可塑性。我们对受体运动特性和作用的理解得益于受体标记和跟踪能力方面的技术进步，以及干扰其运动的新方法。重点关注两个关键的谷氨酸能受体，我们在此回顾了我们对受体运动特征及其在调节突触传递在健康和脑部疾病中的功效的作用的最新理解。受体进出突触的运动已经成为一系列高度调节的过程，介导突触后可塑性。我们对受体运动特性和作用的理解得益于受体标记和跟踪能力方面的技术进步，以及干扰其运动的新方法。重点关注两个关键的谷氨酸能受体，我们在此回顾了我们对受体运动特征及其在调节突触传递在健康和脑部疾病中的功效的作用的最新理解。以及从新的方法来干扰他们的行动。关注两个关键的谷氨酸能受体，我们在这里回顾了我们对受体运动特征及其在调节突触传递在健康和脑部疾病中的功效的作用的最新理解。以及从新的方法来干扰他们的行动。重点关注两个关键的谷氨酸能受体，我们在此回顾了我们对受体运动特征及其在调节突触传递在健康和脑部疾病中的功效的作用的最新理解。