A research team at the Carl Ludwig Institute of Physiology at Leipzig University has shown for the first time how the energy content of individual nerve cells in the brain changes during so-called depolarization waves, waves of activity that occur in various brain diseases. The results provide an important basis for understanding the energy metabolism in the event of an acute lack of blood flow, such as occurs in strokes.
Adenosine triphosphate, or ATP for short, is the central energy carrier in nerve cells. In the current study, scientists from the Carl Ludwig Institute of Physiology used a specially developed mouse line whose nerve cells in the brain produce a fluorescent sensor protein. The nerve cells used this to show how much energy they currently have available. Using high-resolution fluorescence microscopy, the researchers were able to observe live how the ATP content in individual nerve cells changes during the depolarization waves. The depolarization waves in the brain, in which the nerve cells discharge one after the other in a similar way to a short circuit, are associated with progressive tissue damage in strokes. Until now, there have been no studies on how the central energy carrier ATP changes in individual nerve cells during these depolarization waves.
"Our study provides the first high-resolution insight into how and when nerve cells in the brain lose their energy reserves during acute deprivation, such as during a stroke," says Karl Schoknecht from the Carl Ludwig Institute of Physiology, first author of the study. interestingly, the energy reserves are not depleted evenly, but in the course of the depolarization waves. The model is to be used in further projects to test therapeutic approaches for strokes that are intended to prevent the massive loss of energy during depolarization waves," says the scientist from the Faculty of Medicine.
The investigations in the current study show that even in healthy tissue, these waves lead to a short-term drop in the ATP content. The effect of the depolarization waves became particularly clear under conditions of energy deficiency - such as those that prevail during a stroke. Here they massively accelerated the drop in ATP, so that the energy reserves of the nerve cells were depleted. Even after the occurrence of depolarization waves, nerve cells are basically still able to replenish their ATP reserves, provided they are supplied with glucose and oxygen again. The collapse of the energy metabolism can therefore still be reversed in principle.
For the investigations, the team simulated stroke-like conditions by removing glucose and oxygen from the nutrient solution. In parallel, the depolarization waves were recorded using electrophysiological methods. The results are of a basic scientific nature.
The study combines the expertise in state-of-the-art microscopy of Jens Eilers, the development of special mouse models by Johannes Hirrlinger and the research focus on depolarization waves in the brain by Karl Schoknecht at the Carl Ludwig Institute of Physiology.
Original publication in PNAS:
"Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia". DOI: https://doi.org/10.1073/pnas.2415358122
Background:
The Carl Ludwig Institute of Physiology is located at the Medical Faculty of the University of Leipzig and is an international leader in the development of new methods for studying nerve and glial cells. The main areas of research include diseases of the brain and molecular communication in the nervous system. The Institute is integrated into Leipzig University’s research focus areas "Diseases of the brain and soul" and "Molecular and cellular communication".
