The Role of the Glutamate-Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery.

Overview

1. Department of Applied Mathematics, University of Twente, Enschede, the Netherlands
2. Institute of Neurobiology, Heinrich Heine University, Düsseldorf, Germany
3. Clinical Neurophysiology Group, Department of Science and Technology, University of Twente, Enschede, the Netherlands
4. Medisch Spectrum Twente, Enschede, the Netherlands

Abstract

Cerebral ischemia impairs neuronal and glial function, ranging from transient synaptic failure to irreversible damage. The effects of ischemia on excitatory synaptic transmission remain incompletely understood. Here, we present a detailed biophysical model, including the first full implementation of the glutamate–glutamine cycle (GG‐cycle), which is essential for proper functioning of glutamatergic synapses. We model a presynaptic neuron and an astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath as a proxy for energy supply. The model includes ionic currents with corresponding channels and transporters such as the sodium‐potassium ATPase. To model synaptic transmission, we combine calcium‐dependent glutamate release, its uptake by the sodium‐dependent excitatory amino acid transporters (EAATs), and the GG‐cycle, including glutamine synthesis. We simulate ischemia by blocking energy supply completely. This drives the neuron into depolarization block, with pathological ion concentrations and extracellular glutamate accumulation despite disrupted synaptic release. Synaptic transmission failure is not primarily caused by excessive glutamate release or by failure of glutamine synthetase, but mainly results from EAAT dysfunction, driven by the collapse of the sodium gradient. Restoring synaptic transmission is not possible by solely targeting glutamate dynamics but is possible by restoring ion gradients by inhibition of the voltage‐gated Na+‐channel. Our study highlights the critical role of ion homeostasis, in particular the sodium gradient, in failure and recovery of synaptic function and the EAAT during metabolic stress.

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Data

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Data Availability Statement

The code for all the simulations performed is available at https://github.com/HannahvanSusteren3/GGsyntrans.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: — → Wiley

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 6 keywords, 9 MeSH terms, 1 funder, 64 references.

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This paper

van Susteren, H., Rose, C. R., van Putten, M. J. A. M., & Meijer, H. G. E. (2026). The Role of the Glutamate-Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery. The European journal of neuroscience, 64(1), e70604. https://doi.org/10.1111/ejn.70604

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