A Framework for Understanding Power Supply and Demand in Presynaptic Nerve Terminals

The molecular mechanisms of synaptic function and development have been studied extensively, but little is known about the energy requirements of synapses, or the mechanisms that coordinate their energy production with their metabolic demands. These are oversights, as synapses with high energy demands are more susceptible to degeneration and degrade in the early stages of diseases such as amyotrophic lateral sclerosis, spinal muscle atrophy and Parkinson’s disease. Here, in a structure-function study at Drosophila motor neuron terminals, a neurophysiological model was generated to investigate how power (ATP/s) supply is integrated to satisfy the power demand of presynaptic terminals. Power demands were estimated from six nerve terminals through direct measurements of neurotransmitter release and Ca2+ entry, as well as theoretical estimation of Na+ entry and power demands at rest (cost of housekeeping). The data was leveraged with a computational model that simulated the power demands of the terminals during their physiological activity, revealing high volatility in which power demands can increase 15-fold within milliseconds as neurons transition from rest to activity. Another computational model was generated that simulated ATP production scenarios regarding feedback to the power supply machinery (Oxphos and glycolysis) through changes in nucleotide concentrations, showing that feedback from nucleotides alone fail to stimulate power supply to match the power demands of each terminal. Failure of feedback models invokes the need for feed forward mechanisms (such as Ca2+) to stimulate power supply machinery to match power demands. We also quantified mitochondrial volume, density, number and size in each nerve terminal, revealing all four features positively correlate with the terminals power demands. This suggests the terminals enhance their oxidative capacity by increasing mitochondrial content to satisfy their power demands. And lastly, we demonstrate that abolishing an ATP buffering system (the phosphagen system) does not impair neurotransmission in the nerve terminals, suggesting motor nerve terminals are capable of satisfying their power demands without the ATP buffering system.