Energy Disruption in the Brain Linked to Harmful Glutamate Release

The human brain relies heavily on a steady supply of energy to function properly. Disruptions to this energy flow, such as those caused by strokes, can lead to significant complications. Researchers from the Cellular Neurobiology group at Ruhr University Bochum, in collaboration with scholars from the Universities of Düsseldorf and Twente, have explored how energy shortages in the brain influence the release of the neurotransmitter glutamate.

The study indicates that under conditions of stress, abnormal glutamate release events can occur, which may exacerbate nerve cell damage. This research, led by experts in the field, was published in the journal iScience on April 18, 2025.

Typically, brain tissue receives adequate energy, which is essential for the controlled release and reabsorption of neurotransmitters. According to the research, when energy levels plummet, this equilibrium can be disrupted. For instance, during strokes, when blood flow to the brain is compromised, there is often an increase in extracellular glutamate, a situation that severely affects synaptic function and the survival of nerve cells.

Using a novel model system, the researchers identified an unconventional mechanism for glutamate release that significantly elevates its extracellular concentrations during energy depletion. A fluorescent sensor protein was employed to visualize glutamate release in real-time, revealing both conventional neurotransmitter activity and unusual, localized glutamate signals that were larger, longer-lasting, and more variable than typical releases.

Under normal circumstances, such atypical glutamate release events were rare. However, following an induced energy deficiency, their occurrence surged. The research team concluded that these atypical events primarily contribute to the increased extracellular levels of glutamate. Under conditions of metabolic stress, these unusual release events become more prevalent, leading to glutamate accumulation.

In contrast, the regular release of glutamate by neurons, which requires substantial energy, ceased almost entirely during these stress conditions. Previous studies had only noted similar phenomena in models of migraine.

Further experiments demonstrated that heightened extracellular glutamate concentrations could promote additional glutamate release events, indicating a self-reinforcing cycle. Conversely, the researchers found that inhibiting glutamate receptors, particularly a subclass known as NMDA receptors, effectively reduced these atypical release events.

While the study sheds light on the mechanisms behind these unusual neurotransmitter releases, it does not yet clarify which specific cell types are involved. Future research is necessary to determine the extent to which these types of releases impact conditions such as strokes or neurodegenerative diseases. However, it is already well-established that elevated glutamate levels can be detrimental to neurons.