Activity-driven local ATP synthesis is required for synaptic function.

TitleActivity-driven local ATP synthesis is required for synaptic function.
Publication TypeJournal Article
Year of Publication2014
AuthorsRangaraju V, Calloway N, Ryan TA
Date Published2014 Feb 13
KeywordsAdenosine Triphosphate, Animals, Mitochondria, Nerve Tissue Proteins, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, Synapses, Synaptic Vesicles

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 ∼10(6) 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.

Alternate JournalCell
PubMed ID24529383
PubMed Central IDPMC3955179
Grant ListR01 NS036942 / NS / NINDS NIH HHS / United States
R21 NS071293 / NS / NINDS NIH HHS / United States