Available online at www.sciencedirect.com Synaptic stability and plasticity in a floating world Kimberly Gerrow 1,2 and Antoine Triller 1,2 A fundamental feature of membranes is the lateral diffusion of lipids and proteins. Control of lateral diffusion provides a mechanism for regulating the structure and function of synapses. Single-particle tracking (SPT) has emerged as a powerful way to directly visualize these movements. SPT can reveal complex diffusive behaviors, which can be regulated by neuronal activity over time and space. Such is the case for neurotransmitter receptors, which are transiently stabilized at synapses by scaffolding molecules. This regulation provides new insight into mechanisms by which the dynamic equilibrium of receptor–scaffold assembly can be regulated. We will briefly review here recent data on this mechanism, which ultimately tunes the number of receptors at synapses and therefore synaptic strength. Addresses 1 Biologie Cellulaire de la Synapse, Institute de Biologie de l’Ecole Normale Supe ´ rieure (IBENS), 46 rue d’Ulm, 75005 Paris, France 2 Inserm U1024, CNRS UMR, France Corresponding author: Triller, Antoine (triller@biologie.ens.fr) Current Opinion in Neurobiology 2010, 20:631–639 This review comes from a themed issue on New technologies Edited by Erin Schuman and Xiaowei Zhuang Available online 23rd July 2010 0959-4388/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.conb.2010.06.010 Introduction The concept of diffusion, rooted in physical science, is now being applied to biological systems. Diffusion of a molecule in the plasma membrane can be measured by single-particle tracking (SPT) (Box 1). Advances in micro- scopy and the production of smaller and better probes for SPT have led to a recent explosion in understanding of how diffusion affects numerous neuronal processes. Description of SPT implementation, including molecule labeling, image acquisition, data treatment, and analysis of diffusion properties, has already been addressed in detail [1,2]. Study of the diffusive properties of molecules by SPT, and in particular neurotransmitter receptors, has greatly reshaped our understanding of molecular traffick- ing in neurons. The number of neurotransmitter receptors at a synapse is a key element determining synaptic transmission efficacy. Exocytosis and endocytosis play a role in determining the number of receptors on the membrane surface and at synapses (reviewed in [3,4]). This receptor cycling between intracellular compartments and the membrane surface is crucial for maintaining a mobile population of surface receptors that can be deliv- ered to synapses via lateral diffusion [5  ]. SPT experiments have demonstrated that receptors can exchange rapidly between the synaptic and extrasynaptic compartments, and that transient stabilization of receptors at synapses can occur by interaction with binding partners, such as scaffold proteins. This phenomenon, referred to as a ‘dif- fusion trap’, operates at both excitatory and inhibitory synapses [6,7]. Thus, the regulations of receptor-scaffold and scaffold–scaffold interactions are one of the central mechanisms for the maintenance and plasticity-related changes of receptor number at synapses. Cohesion by lateral diffusion: synapse stability despite mobility Though synapses are stable on a long time scale, the individual molecules of a synapse turn over on a shorter time scale, even at steady state. Both receptors and scaffolding proteins can turn over within tens of minutes (reviewed in [8]). Numerous transient interactions be- tween synaptic components maintain a synaptic connec- tion, despite this continual exchange of the individual constitutive elements. This has led to the concept of the synapse as a multimolecular assembly, the dynamics of which is governed by diffusion-reaction processes [6,7]. As a consequence, the various interactions between synaptic molecular components can then be described as akin to chemical reactions, characterized by their K on and K off . The combination of these reactions can account, at least in part, for the residence (dwell) time of a given molecule in the synaptic multimolecular complex. The complexity of this phenomenon relies on the fact that molecular interactions are not straightforward. Multiple association states between molecules exist, defined by different affinities and rates of association/dissociation (Figure 1). These various states on the one hand introduce nonlinearity and complexity to the relationship between affinities and dwell time of a molecule at the synapse, and on the other hand offer multiple levels of regulation to fine tune their association. In such a model, weak interactions would be more biologically relevant than strong ones, since the latter are less likely to be easily modified. Actually, traditional biochemical methods which study protein inter- action ex vivo, such as affinity chromatography and immu- noprecipitation, tend to emphasize these strong affinities in protein interactions. In contrast, study of protein interactions by SPT allows access to molecular biochem- istry in living cells, as well as the appreciation of weak interactions that may have profound biological signifi- cance. For instance, biochemical methods have shown www.sciencedirect.com Current Opinion in Neurobiology 2010, 20:631–639