Cell survival depends on the energy molecule adenosine triphosphate (ATP) - it's like the fuel that keeps our brain running. Intracellular ATP levels are thought to remain constant, given its importance. To maintain this stability, the brain strikes a delicate balance between metabolic energy supply and how much energy our brain is using (neuronal activity).
Purposely causing an imbalance in this carefully regulated system and observing the effects can reveal surprising insights. Researchers from Tohoku University challenged the mouse brain with a metabolic load induced by epileptic seizures, and observed fluctuations in blood volume, astrocytic pyruvate, and neuronal ATP. They found that a single epileptic seizure could greatly reduce ATP. This finding may help redefine our understanding of brain energy dynamics, and how it impacts individuals with epilepsy.
The findings were published in the Journal of Neurochemistry on March 20, 2025.
An optical fiber inserted into the hippocampus of mice allowed the researchers to visualize fluorescent ATP, or pyruvate sensors in neurons or astrocytes, respectively, to measure fluctuations in these metabolites. A train of electrical stimulation in the hippocampus induced a hyperactive response resembling epileptic seizures. In response, ATP levels in neurons decreased, while pyruvate levels in astrocytes increased.
The brain accounts for 2% of body mass but consumes 20% of the body's total glucose. Although glucose and oxygen are supplied to the brain through blood vessels, neurons don't directly contact these vessels--astrocytes do. Astrocytes take up glucose, convert it into pyruvate, and then into lactate. The lactate is released and later taken up by neurons, which convert it back into pyruvate to produce ATP. During the induced epileptic seizure, it is possible that this lactate shuttle was temporarily shut down, causing an accumulation of excess pyruvate in astrocytes and a decrease in neuronal ATP.
The same stimulation leads to varying lengths of neuronal hyperactivity (after discharges; ADs). Although a prolonged AD would typically consume more energy, they found that the reduction in neuronal ATP remained the same. Interestingly, the reduction in neuronal ATP levels decreased as epilepsy developed, while the local blood volume increased. This rise in metabolic energy supply may partially compensate for the loss of ATP in neurons.
These results suggest that the supply of energy molecules from blood vessels and astrocytes may play a much more significant role in determining ATP levels than previously thought.
"We believe this could change how we understand energy management in the brain," says Professor Ko Matsui of Tohoku University. "The key to understanding the brain's super energy-saving, information-processing capabilities may lie in studying the neuron-metabolic system."
Lead investigator Kota Furukawa believes understanding brain energy dynamics could be the key to treating brain diseases. "This may just be a glimpse of how astrocytes and blood vessels affect epilepsy pathology," Furukawa explains. "An intricate neuron-metabolic system provides stable energy for daily information processing. A glitch in this system could underlie numerous brain diseases - not just epilepsy, but also mental illnesses."
Journal of Neurochemistry
Dynamics of neuronal and astrocytic energy molecules in epilepsy
20-Mar-2025