Savtchenko, Leonid P;
Rusakov, Dmitri A;
(2023)
Glutamate–Transporter Unbinding in Probabilistic Synaptic Environment Facilitates Activation of Distant NMDA Receptors.
Cells
, 12
(12)
, Article 1610. 10.3390/cells12121610.
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Abstract
Once outside the synaptic cleft, the excitatory neurotransmitter glutamate is rapidly bound by its high-affinity transporters, which are expressed in abundance on the surface of perisynaptic astroglia. While this binding and the subsequent uptake of glutamate constrain excitatory transmission mainly within individual synapses, there is growing evidence for the physiologically important extrasynaptic actions of glutamate. However, the mechanistic explanation and the scope of such actions remain obscure. Furthermore, a significant proportion of glutamate molecules initially bound by transporters could be released back into the extracellular space before being translocated into astrocytes. To understand the implications of such effects, we simulated the release, diffusion, and transporter and receptor interactions of glutamate molecules in the synaptic environment. The latter was represented via trial-by-trial stochastic generation of astroglial and neuronal elements in the brain neuropil (overlapping spheroids of varied sizes), rather than using the ‘average’ morphology, thus reflecting the probabilistic nature of neuropil architectonics. Our simulations predict significant activation of high-affinity receptors, such as receptors of the NMDA type, at distances beyond half-micron from the glutamate release site, with glutamate–transporter unbinding playing an important role. These theoretical predictions are consistent with recent glutamate imaging data, thus lending support to the concept of significant volume-transmitted actions of glutamate in the brain.
| Type: | Article |
|---|---|
| Title: | Glutamate–Transporter Unbinding in Probabilistic Synaptic Environment Facilitates Activation of Distant NMDA Receptors |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/cells12121610 |
| Publisher version: | https://doi.org/10.3390/cells12121610 |
| Language: | English |
| Additional information: | Copyright © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | glutamate spillover; astrocyte; glutamate uptake; GLT-1; extrasynaptic actions; probabilistic synaptic model; Monte Carlo simulations |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10172582 |
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