Cell
Volume 156, Issue 4, 13 February 2014, Pages 825-835
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Article
Activity-Driven Local ATP Synthesis Is Required for Synaptic Function

https://doi.org/10.1016/j.cell.2013.12.042Get rights and content
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Highlights

  • A genetically encoded optical reporter of ATP has been developed

  • During electrical activity, energy demands are met by activity-driven ATP synthesis

  • The synaptic vesicle cycle is the major consumer of ATP

  • Compromising routes of ATP synthesis rapidly and severely impair synaptic function

Summary

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.

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