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A research team at the Carl Ludwig Institute for Physiology at Leipzig University has,for the first time, demonstrated how the energy levels of individual neurons in the brain change during so-called spreading depolarizations – waves of activity that occur in various brain disorders. The findings provide important foundations for understanding energy metabolism in cases of acute cerebral ischaemia, such as that which occurs during a stroke. The study has just been published in the renowned journal PNAS.
Adenosine triphosphate, or ATP, is an essential energy source in neurons. In the new study, researchers at the Carl Ludwig Institute for Physiology used a specially developed mouse model whose brain neurons produce a fluorescent sensor protein. This allowed them to visualise the available amount of energy in individual neurons. Using high-resolution fluorescence microscopy, the team was able to observe, in real time, how ATP levels in single neurons changed during spreading depolarizations. These waves – in which neurons depolarize one after another, much like a short circuit – are linked to progressive tissue damage after stroke. Until now, it was unclear how ATP, the brain’s central energy carrier, behaves in individual neurons during such waves.
“Our study is the first to provide high-resolution insights into how and when neurons lose their energy reserves during an acute mismatch between energy supply and demand, such as in a stroke,” says Dr Karl Schoknecht of the Carl Ludwig Institute for Physiology, lead author of the study. “Interestingly, the energy reserves are not depleted evenly, but associated with spreading depolarizations. The model will be used in further projects to test potential therapies aimed at preventing the severe energy loss triggered by these waves,” explains the researcher from the Faculty of Medicine.
The findings of the study show that even in ‘healthy’ brain tissue, these waves cause a temporary drop in ATP levels. The effect of spreading depolarizations became particularly pronounced under conditions of energy deprivation – like those that occur during a stroke. In such cases, the waves greatly accelerated the loss of ATP, leading to the exhaustion of the neurons’ energy reserves. However, even after spreading depolarizations, most neurons were still capable of replenishing their ATP stores – provided that glucose and oxygen were resupplied. This means that the collapse of energy metabolism is, in principle, still reversible.
In this study, the team simulated stroke conditions by removing glucose and oxygen from the nutrient solution. At the same time, they recorded spreading depolarizations using electrophysiological methods. The findings contribute to the understanding of brain energy metabolism.
The study brings together complementary expertise at the Carl Ludwig Institute for Physiology: advanced microscopy from Professor Jens Eilers, the development of specialised mouse models by Professor Johannes Hirrlinger, and Dr Karl Schoknecht’s research on spreading depolarizations.
Background:
The Carl Ludwig Institute for Physiology is part of the Faculty of Medicine at Leipzig University and is internationally recognised for its pioneering work in developing new methods to study nerve and glial cells. Its research focuses include brain disorders and molecular communication within the nervous system. The Institute contributes to two of Leipzig University’s key research areas: Brain and Psychological Disorders, and Molecular and Cellular Communication.
Translation: Matthew Rockey
Dr Karl Schoknecht
Carl Ludwig Institute for Physiology, Faculty of Medicine
Leipzig University
karl.schoknecht@medizin.uni-leipzig.de
Original publication in PNAS: “Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia”. DOI: https://doi.org/10.1073/pnas.2415358122
Using high-resolution fluorescence microscopy, the researchers were able to observe live how the ATP ...
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Using high-resolution fluorescence microscopy, the researchers were able to observe live how the ATP ...
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