Activity-Driven Local ATP Synthesis Is Required for Synaptic Function

TLDR

Cognitive function is tightly linked to metabolic state, yet the locus of this control is unclear, and although synapses have large ATP demands, how fuel availability and electrical activity influence synaptic ATP levels and function remains unknown. The authors employed a genetically encoded optical reporter, Syn‑ATP, to demonstrate that electrical activity imposes large metabolic demands that are met through activity‑driven regulation of glycolysis and mitochondrial function. They discovered that the synaptic vesicle cycle is the primary source of activity‑driven metabolic demand, that activity‑driven ATP synthesis supplies roughly 10⁶ free ATPs per nerve terminal, yet brief interruptions in ATP synthesis severely impair key presynaptic functions.

Abstract

Cognitive function is tightly related to metabolic state, but the locus of this control is not well understood. Synapses are thought to present large ATP demands; however, it is unclear how fuel availability and electrical activity impact synaptic ATP levels and how ATP availability controls synaptic function. We developed a quantitative genetically encoded optical reporter of presynaptic ATP, Syn-ATP, and find that electrical activity imposes large metabolic demands that are met via activity-driven control of both glycolysis and mitochondrial function. We discovered that the primary source of activity-driven metabolic demand is the synaptic vesicle cycle. In metabolically intact synapses, activity-driven ATP synthesis is well matched to the energetic needs of synaptic function, which, at steady state, results in ∼106 free ATPs per nerve terminal. Despite this large reservoir of ATP, we find that several key aspects of presynaptic function are severely impaired following even brief interruptions in activity-stimulated ATP synthesis.