Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy

Abstract

The dynamics of energy molecules in the mouse brain during metabolic challenges induced by epileptic seizures were examined. A transgenic mouse line expressing a fluorescence resonance energy transfer (FRET)-based adenosine triphosphate (ATP) sensor, selectively expressed in the cytosol of neurons, was used. An optical fiber was inserted into the hippocampus, and changes in cytosolic ATP concentration were estimated using the fiber photometry method. To induce epileptic neuronal hyperactivity, a train of electrical stimuli was delivered to a bipolar electrode placed alongside the optical fiber. Although maintaining a steady cytosolic ATP concentration is crucial for cell survival, a single episode of epileptic neuronal hyperactivity drastically reduced neuronal ATP levels. Interestingly, the magnitude of ATP reduction did not increase with the exacerbation of epilepsy, but rather decreased. This suggests that the primary consumption of ATP during epileptic neuronal hyperactivity may not be solely directed toward restoring the Na⁺ and K⁺ ionic imbalance caused by action potential bursts. Cytosolic ATP concentration reflects the balance between supply and consumption. To investigate the metabolic flux leading to neuronal ATP production, a new FRET-based pyruvate sensor was developed and selectively expressed in the cytosol of astrocytes in transgenic mice. Upon epileptic neuronal hyperactivity, an increase in astrocytic pyruvate concentration was observed. Changes in the supply of energy molecules, such as glucose and oxygen, due to blood vessel constriction or dilation, as well as metabolic alterations in astrocyte function, may contribute to cytosolic ATP dynamics in neurons.