An aggregation-removal model for the formation and size determination of post-synaptic scaffold domains

Jonas Ranft,Antoine Triller,Pamela C Rodriguez,Leandro G Almeida,Vincent Hakim,Francesco P Battaglia

doi:10.1371/journal.pcbi.1005516

Abstract

The formation and stability of synapses are key questions in neuroscience. Post-synaptic domains have been classically conceived as resulting from local insertion and turnover of proteins at the synapse. However, insertion is likely to occur outside the post-synaptic domains and advances in single-molecule imaging have shown that proteins diffuse in the plane of the membrane prior to their accumulation at synapses. We quantitatively investigated this scenario using computer simulations and mathematical analysis, taking for definiteness the specific case of inhibitory synapse components, i.e., the glycine receptor (GlyR) and the associated gephyrin scaffolding protein. The observed domain sizes of scaffold clusters can be explained by a dynamic balance between the aggregation of gephyrin proteins diffusing while bound to GlyR and their turnover at the neuron membrane. We also predict the existence of extrasynaptic clusters with a characteristic size distribution that significantly contribute to the size fluctuations of synaptic domains. New super-resolution data for gephyrin proteins established the existence of extrasynaptic clusters the sizes of which are consistent with the model predictions in a range of model parameters. At a general level, our results highlight aggregation with removal as a non-equilibrium phase separation which produces structures of tunable size.

Highlights

Synapses mediate transmission of information between neurons and are generally thought to be, at least in part, the support of memory
It has been realized that synapses are dynamic biological structures
We propose a biophysical model that links these different measured quantities for inhibitory synapse components and show how they determine the size of postsynaptic domains

Summary

Introduction

Synapses mediate transmission of information between neurons and are generally thought to be, at least in part, the support of memory. When investigated at the molecular scale, synapses appear as dynamic assemblies, the constituents of which are exchanged on timescales ranging from tens of minutes down to seconds [1]. This raises fundamental questions about the way memory is maintained [2]. The strength of a synapse is determined by the number of receptors at the PSD at a given moment This number depends on the number of receptor binding sites provided by the scaffolding proteins [6] as well as on the affinity between receptors and scaffolding proteins [7]. The size of the PSD, i.e., the number of scaffold protein binding sites, is a key determinant of synaptic strength

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Conclusion