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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
JournalCell
Volume156
Issue4
Pagination825-35
Date Published2014 Feb 13
ISSN1097-4172
KeywordsAdenosine Triphosphate, Animals, Mitochondria, Nerve Tissue Proteins, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, Synapses, Synaptic Vesicles
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 ∼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.

DOI10.1016/j.cell.2013.12.042
Alternate JournalCell
PubMed ID24529383
PubMed Central IDPMC3955179
Grant ListR01 NS036942 / NS / NINDS NIH HHS / United States
R21 NS071293 / NS / NINDS NIH HHS / United States