Presynaptic ATP Decreases During Physiological-Like Activity in Neurons Tuned for High-Frequency Transmission.

Area of Science:

• Neuroscience
• Cellular Biology
• Biochemistry

Background:

• Neuronal activity requires stable adenosine triphosphate (ATP) concentrations, maintained by activity-dependent ATP production.
• Mechanisms governing activity-dependent ATP production, whether feedforward or feedback, remain debated.
• Feedforward mechanisms do not necessitate changes in ATP/ADP levels, while feedback mechanisms may be triggered by nucleotide concentration shifts.

Purpose of the Study:

• To investigate the role of feedback mechanisms in regulating ATP concentration during neuronal activity.
• To quantify ATP concentration changes in presynaptic terminals under varying synaptic activity levels.
• To provide quantitative constraints for models of activity-dependent ATP production.

Main Methods:

• Utilized genetically encoded ATP sensors in acute brain slices and in vivo recordings from mouse models.
• Focused on cerebellar mossy fiber boutons (cMFB) and the calyx of Held, specialized for high-frequency transmission.
• Performed experiments with blockade of ATP production and quantitative modeling of feedback mechanisms.

Main Results:

• Resting ATP concentration in cMFBs was approximately 2.5-2.7 mM at physiological conditions.
• Neuronal activity, even at physiological levels, caused a measurable decrease in ATP concentration (~150 μM).
• ATP production increased ~10-fold during activity, and ADP-based feedback models could explain observed ATP dynamics.

Conclusions:

• ATP concentration can decrease in presynaptic terminals during physiological-like neuronal activity.
• Data support the existence of feedback mechanisms, possibly ADP-dependent, in regulating ATP production.
• Findings suggest that ATP levels are not always stable and can fluctuate during neural signaling.