Quantifying the Effects of Elastic Collisions and Non-Covalent Binding on Glutamate Receptor Trafficking in the Post-Synaptic Density

Fidel Santamaria,Jossina Gonzalez,Sridhar Raghavachari,George J Augustine,James M Briggs

doi:10.1371/journal.pcbi.1000780

Abstract

One mechanism of information storage in neurons is believed to be determined by the strength of synaptic contacts. The strength of an excitatory synapse is partially due to the concentration of a particular type of ionotropic glutamate receptor (AMPAR) in the post-synaptic density (PSD). AMPAR concentration in the PSD has to be plastic, to allow the storage of new memories; but it also has to be stable to preserve important information. Although much is known about the molecular identity of synapses, the biophysical mechanisms by which AMPAR can enter, leave and remain in the synapse are unclear. We used Monte Carlo simulations to determine the influence of PSD structure and activity in maintaining homeostatic concentrations of AMPARs in the synapse. We found that, the high concentration and excluded volume caused by PSD molecules result in molecular crowding. Diffusion of AMPAR in the PSD under such conditions is anomalous. Anomalous diffusion of AMPAR results in retention of these receptors inside the PSD for periods ranging from minutes to several hours in the absence of strong binding of receptors to PSD molecules. Trapping of receptors in the PSD by crowding effects was very sensitive to the concentration of PSD molecules, showing a switch-like behavior for retention of receptors. Non-covalent binding of AMPAR to anchored PSD molecules allowed the synapse to become well-mixed, resulting in normal diffusion of AMPAR. Binding also allowed the exchange of receptors in and out of the PSD. We propose that molecular crowding is an important biophysical mechanism to maintain homeostatic synaptic concentrations of AMPARs in the PSD without the need of energetically expensive biochemical reactions. In this context, binding of AMPAR with PSD molecules could collaborate with crowding to maintain synaptic homeostasis but could also allow synaptic plasticity by increasing the exchange of these receptors with the surrounding extra-synaptic membrane.

Highlights

Ligand-gated neurotransmitter receptors in the post-synaptic membrane respond to neurotransmitter release and thereby mediate rapid signaling at neuronal synapses
Since the effects of increasing molecular crowding could be classified as binding to static post-synaptic density (PSD) molecules, we examined the potential contribution of the PSD molecules to the retention of amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) inside the PSD
We studied the general principle of how transient alterations in binding of PSD molecules can affect the concentration of AMPAR in the context of molecular crowding

Summary

Introduction

Ligand-gated neurotransmitter receptors in the post-synaptic membrane respond to neurotransmitter release and thereby mediate rapid signaling at neuronal synapses. Efficient synaptic signaling demands that these receptors be concentrated at high densities in order to optimally respond to rapidly diffusing neurotransmitter molecules. AMPARs are concentrated in a large membrane-associated protein complex called the post-synaptic density (PSD) [3]. While in the extra-synaptic membrane AMPARs undergo lateral diffusion and are randomly captured by the PSD through direct and indirect biochemical interactions with multiple partners [6,7,8,9,10,11]. AMPARs bind to scaffolding proteins in the PSD it seems that biochemical interactions alone cannot explain the retention of AMPARs required to achieve long lasting changes in synaptic strength. Genetic manipulation of PSD scaffolding protein levels does not abolish basal synaptic transmission and leaves the amplitude of spontaneous excitatory potentials unchanged [14,15,16]

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