title: Activity-driven local ATP synthesis is required for synaptic function.
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.
authors: Rockefeller/Sloan-Kettering/Weill Cornell Tri-Institutional Training Program in Chemical Biology, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Vidhya
authors: V
authors: Rangaraju
authors: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Nathaniel
authors: N
authors: Calloway
authors: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: taryan@med.cornell.edu.
authors: Timothy A
authors: TA
authors: Ryan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; C103912:Unc13a protein, rat; D000255:Adenosine Triphosphate