Buffering by Transporters Can Spare Geometric Hindrance in Controlling Glutamate Escape.

Leonid P Savtchenko,Dmitri A Rusakov,Kaiyu Zheng

doi:10.3389/fncel.2021.707813

Abstract

The surface of astrocyte processes that often surround excitatory synapses is packed with high-affinity glutamate transporters, largely preventing extrasynaptic glutamate escape. The shape and prevalence of perisynaptic astroglia vary among brain regions, in some cases providing a complete isolation of synaptic connections from the surrounding tissue. The perception has been that the geometry of perisynaptic environment is therefore essential to preventing extrasynaptic glutamate escape. To understand to what degree this notion holds, we modelled brain neuropil as a space filled with a scatter of randomly sized, overlapping spheres representing randomly shaped cellular elements and intercellular lumen. Simulating release and diffusion of glutamate molecules inside the interstitial gaps in this medium showed that high-affinity transporters would efficiently constrain extrasynaptic spread of glutamate even when diffusion passages are relatively open. We thus estimate that, in the hippocampal or cerebellar neuropil, the bulk of glutamate released by a synaptic vesicle is rapidly bound by transporters (or high-affinity target receptors) mainly in close proximity of the synaptic cleft, whether or not certain physiological or pathological events change local tissue geometry.

Highlights

Glutamatergic circuitry of the brain has long been associated with a “wired,” one-to-one type of transmission that carries excitatory signals between individual nerve cells
To ensure that glutamate released into the synaptic cleft does not escape activating its receptors beyond the target cell, excitatory synapses are often surrounded by perisynaptic astrocyte processes (PAPs), part of the sponge-like morphology of brain astroglia
To understand how this would affect the scatter of glutamate molecules away from the release site, we simulated brain neuropil as a space filled by randomly sized, overlapping spheres representing cellular structures: this procedure formed a porous, randomly shaped medium, with volume fraction β occupied by spheres, or porosity α = 1-β (Savtchenko et al, 2021)

Summary

Introduction

Glutamatergic circuitry of the brain has long been associated with a “wired,” one-to-one type of transmission that carries excitatory signals between individual nerve cells. It has often been argued that the synapse has to Glutamate Buffering Spares Geometry be comprehensively surrounded by the transporter-enriched PAPs, to prevent synaptically released glutamate from spilling over to the neighbouring tissue Whilst the latter would stop glutamate from escaping, whether the commonly observed partial PAP coverage is as effective in this respect has remained uncertain, prompting intense theoretical and experimental exploration of extrasynaptic glutamate escape (Diamond, 2001; Rusakov, 2001; Scimemi et al, 2004; Szapiro and Barbour, 2007; Zheng et al, 2008; Scimemi et al, 2009; Henneberger et al, 2020)

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