Our brain requires a constant supply of energy. A disrupted energy supply, as it is for instance caused by a stroke, can have serious complications. A team from the research group Cellular Neurobiology at Ruhr University Bochum, Germany, together with researchers from the Universities of Düsseldorf and Twente, investigated how an energy deficiency in the brain affects the release of the neurotransmitter glutamate. They observed that under stress abnormal glutamate release events occur that self-amplify and that may thereby contribute to the damage of nerve cells. The researchers, led by Dr. Tim Ziebarth, report their findings in the journal iScience on April 18, 2025.

Under normal conditions, brain tissue is sufficiently supplied with energy, which is in part required for the selective release and reuptake of neurotransmitters. “However, if there is no longer enough energy available, this balance between neurotransmitter release and reuptake can quickly become disrupted,” Tim Ziebarth explains. “Especially in the case of strokes, where the blood supply to the brain is interrupted, there is often an extracellular increase in the excitatory neurotransmitter glutamate, which severely impairs the function of synapses and the survival of the affected nerve cells.” However, the underlying processes are only partially understood.

Using a model system, Tim Ziebarth observed a previously unknown, unconventional release mechanism that significantly increased the extracellular glutamate concentrations upon energy depletion. For his measurements, he used a fluorescent sensor protein, which allowed him to visualize the release of glutamate in real-time. In addition to regular glutamate releases, which are typical for the synaptic activity of neurons, he also observed very unusual, local glutamate signals that were relatively large, long-lasting, and heterogeneous. “Under normal conditions, these atypical events occurred only sporadically,” he reports. “However, after inducing an energy deficiency, their frequency increased significantly.”

Ultimately, these events were the main cause of the increase in extracellular glutamate concentration. “It seems that under metabolic stress conditions, such as energy depletion, these atypical release events are particularly favored, which led to the accumulation of glutamate,” Professor Andreas Reiner concludes. “In contrast, the normal glutamate release by neurons, which itself requires substantial amounts of energy, came to a halt.” Similar observations had previously only been described for a migraine model.

In further experiments, the team was able to show that increased extracellular glutamate concentrations promoted additional release events. The process is therefore self-reinforcing. Conversely, the researchers were able to significantly reduce this type of glutamate release by inhibiting glutamate receptors, especially by inhibiting the subclass of NMDA receptors.

The study does not yet answer exactly how the unusual neurotransmitter releases occur and which cell types are responsible. “Further investigations must also clarify how much this type of release actually contributes in stroke situations or in neurodegenerative diseases,” says Andreas Reiner. However, it is well established that elevated glutamate concentrations are harmful to neurons.