Linking glutamate receptor movements and synapse function

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.