Local glutamate-glutamine cycling underlies presynaptic ATP homeostasis

Presynaptic axon terminals maintain in their cytosol an almost constant level of adenosine triphosphate (ATP) to safeguard neurotransmission during varying workloads. In the present study, it is argued that the vesicular release of neurotransmitter,and the recycling of transmitter via astrocytes, may itself be a mechanism of ATP homeostasis.In a minimal metabolic model of a presynaptic axon bouton, the accumulation of glutamate into vesicles and the activity-dependent supply of its precursor glutamine by astrocytes generated a steady-state level of ATP that was independent of the workload. When the workload increased, an enhanced supply of glutamine raised the rate of ATP production through the conversion of glutamate to the Krebs cycle intermediate alpha-ketoglutarate. The accumulation and release of glutamate, on the other hand, acted as a leak that diminished ATP production when the workload decreased. The fraction of ATP which the axon spent on the release and recycling of glutamate was small (4.7 %), irrespective of the workload. Increasing this fraction enhanced the speed of ATP homeostasis, and reduced the futile production of ATP. The model can be extended to axons releasing other, or coreleasing multiple, transmitters. Hence, the activity-dependent formation and release of neurotransmitter may be a universal mechanism of ATP homeostasis.