Title | Activity-driven local ATP synthesis is required for synaptic function. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Rangaraju V, Calloway N, Ryan TA |
Journal | Cell |
Volume | 156 |
Issue | 4 |
Pagination | 825-35 |
Date Published | 2014 Feb 13 |
ISSN | 1097-4172 |
Keywords | Adenosine 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. |
DOI | 10.1016/j.cell.2013.12.042 |
Alternate Journal | Cell |
PubMed ID | 24529383 |
PubMed Central ID | PMC3955179 |
Grant List | R01 NS036942 / NS / NINDS NIH HHS / United States R21 NS071293 / NS / NINDS NIH HHS / United States |