|Activity-driven local ATP synthesis is required for synaptic function.
|Year of Publication
|Rangaraju V, Calloway N, Ryan TA
|2014 Feb 13
|Adenosine 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.
|PubMed Central ID
|R01 NS036942 / NS / NINDS NIH HHS / United States
R21 NS071293 / NS / NINDS NIH HHS / United States