Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse
Open accessAbstract
KEY POINTS: Synapses have high energy demands which increase during intense activity. We show that presynaptic terminals can utilise extracellular glucose or lactate to generate energy to maintain synaptic transmission. Reducing energy substrates induces a metabolic stress: presynaptic ATP depletion impaired synaptic transmission through a reduction in the number of functional synaptic vesicle release sites and a slowing of vesicle pool replenishment, without a consistent change in release probability. Metabolic function is compromised in many pathological conditions (e.g. stroke, traumatic brain injury and neurodegeneration). Knowledge of how synaptic transmission is constrained by metabolic stress, especially during intense brain activity, will provide insights to improve cognition following pathological insults. ABSTRACT: The synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 mm) as the extracellular substrates while inducing metabolic stress. High-frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage-clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCTs). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high-intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low.
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Either glucose or lactate can support transmission at high-frequency auditory presynaptic terminals.
“Either glucose or lactate can support transmission at high-frequency auditory presynaptic terminals (Lucas et al., 2018);”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Lucas et al., 2018
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Research works printed but not linked: 1
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Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism
Yellen, G. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201803152 · Cited by 371 · see citing works
“Either glucose or lactate can support transmission at high-frequency auditory presynaptic terminals (Lucas et al., 2018); this study argued for lactate shuttling under limited conditions, but this conclusion is weak because MCT blockers that would also block mitochondrial pyruvate uptake were used…”
BackgroundMethod
- Authors
- Lucas, S. J., Michel, C. B., Marra, V., Smalley, J. L., Hennig, M. H., Graham, B. P., & Forsythe, I. D.
- Affiliations
- University of Leicester (GB)
- University of Stirling (GB)
- Tufts University (US)
- University of Edinburgh (GB)
- Corresponding author
- Forsythe, Ian D.
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2018-03-26
- Volume
- 596
- Issue
- 9
- Pages
- 1699-1721
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC5924824
- OpenAlex
- W2788486909
- Cited by
- 39
- References
- 64
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 8 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 3
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Stirling Online Research Repository (University of Stirling) (submittedVersion, public-domain)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Medical Research Council (MR/K005170/1)
- Wellcome Trust (unknown)
- Biotechnology and Biological Sciences Research Council (BB/K01899X/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- glucose, lactate, synaptic transmission, calyx of Held, excitatory synapses, synaptic vesicle recycling, release sites, release probability, metabolic stress, monocarboxylate transporters, glycogenolysis, astrocytes, high-frequency stimulation
- MeSH terms
- Action Potentials, Animals, Brain Stem, Female, Glucose, Male, Mice, Inbred CBA, Synaptic Transmission, Synapses, Presynaptic Terminals, Lactic Acid, Mice
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