Activity-driven local ATP synthesis is required for synaptic function
Open accessAbstract
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.
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In presynaptic terminals, both glycolysis and oxphos appear important for managing intense activity.
“In presynaptic terminals, both glycolysis and oxphos appear important for managing intense activity (Rangaraju et al., 2014; Sobieski et al., 2017).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Rangaraju et al., 2014
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- Authors
- Rangaraju, V., Calloway, N., & Ryan, T. A.
- Affiliations
- Cornell University (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Ryan, Timothy A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 156
- Issue
- 4
- Pages
- 825-835
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3955179
- OpenAlex
- W1967646152
- Cited by
- 836
- References
- 40
- Citations by year
- 2026: 92 · 2025: 101 · 2024: 72 · 2023: 83 · 2022: 75 · 2021: 82 · 2020: 63 · 2019: 66 · 2018: 66 · 2017: 55 · 2016: 37 · 2015: 32 · 2014: 11 · 2013: 1
- FWCI
- 20.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Weill Cornell Medical College
- National Institute of Neurological Disorders and Stroke (R21NS071293, R01NS036942)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- glycolysis, mitochondrial function, synaptic vesicle recycling, presynaptic function, presynaptic terminals, ATP availability
- MeSH terms
- Adenosine Triphosphate, Animals, Mitochondria, Nerve Tissue Proteins, Synapses, Synaptic Vesicles, Rats, Sprague-Dawley, Presynaptic Terminals, Rats
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