Novel Model of Neuronal Bioenergetics: Postsynaptic Utilization of Glucose but not Lactate Correlates Positively with Ca 2+ Signalling in Cultured Mouse Glutamatergic Neurons
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We have previously investigated the relative roles of extracellular glucose and lactate as fuels for glutamatergic neurons during synaptic activity. The conclusion from these studies was that cultured glutamatergic neurons utilize glucose rather than lactate during NMDA (N-methyl-d-aspartate)-induced synaptic activity and that lactate alone is not able to support neurotransmitter glutamate homoeostasis. Subsequently, a model was proposed to explain these results at the cellular level. In brief, the intermittent rises in intracellular Ca2+ during activation cause influx of Ca2+ into the mitochondrial matrix thus activating the tricarboxylic acid cycle dehydrogenases. This will lead to a lower activity of the MASH (malate-aspartate shuttle), which in turn will result in anaerobic glycolysis and lactate production rather than lactate utilization. In the present work, we have investigated the effect of an ionomycin-induced increase in intracellular Ca2+ (i.e. independent of synaptic activity) on neuronal energy metabolism employing 13C-labelled glucose and lactate and subsequent mass spectrometric analysis of labelling in glutamate, alanine and lactate. The results demonstrate that glucose utilization is positively correlated with intracellular Ca2+ whereas lactate utilization is not. This result lends further support for a significant role of glucose in neuronal bioenergetics and that Ca2+ signalling may control the switch between glucose and lactate utilization during synaptic activity. Based on the results, we propose a compartmentalized CiMASH (Ca2+-induced limitation of the MASH) model that includes intracellular compartmentation of glucose and lactate metabolism. We define pre- and post-synaptic compartments metabolizing glucose and glucose plus lactate respectively in which the latter displays a positive correlation between oxidative metabolism of glucose and Ca2+ signalling.
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Direct neuronal glycolysis is recruited in response to stimulation in a relatively intact system.
“The inferred recruitment of direct neuronal glycolysis in response to stimulation in a relatively intact system is consistent with earlier carbon tracing studies on cultured neurons (Bak et al., 2009, 2012).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Bak et al., 2012
Moderate chemical stimulation produced a strong increase in labeling of glutamate from labeled glucose and a decrease in incorporation of label from labeled lactate, inconsistent with significant lactate utilization by neurons during stimulation.
“Moderate chemical stimulation produced a strong increase in the labeling of glutamate from labeled glucose and a decrease in the incorporation of label from labeled lactate, inconsistent with significant lactate utilization by neurons during stimulation.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Bak et al., 2012
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Self-citation
- Authors
- Bak, L. K., Obel, L. F., Walls, A. B., Schousboe, A., Faek, S. A. A., Jajo, F. S., & Waagepetersen, H. S.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Bak, Lasse K.
- Venue
- ASN NEURO
- Publisher
- Informa UK Limited
- Published
- 2012-03
- Volume
- 4
- Issue
- 3
- ISSN
- 1759-0914 (ISSN-L)
- PMC
- PMC3320216
- OpenAlex
- W2008661541
- Cited by
- 45
- References
- 30
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 3 · 2014: 5 · 2013: 6 · 2012: 3
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ASN NEURO (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- 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 › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- neuronal bioenergetics, glucose utilization, lactate utilization, calcium signaling, glutamatergic neurons, malate-aspartate shuttle, glutamate homeostasis, anaerobic glycolysis
- MeSH terms
- Animals, Energy Metabolism, Glucose, Intracellular Fluid, Mice, Inbred C57BL, Models, Neurological, Synaptic Transmission, Neurons, PC12 Cells, Glutamic Acid, Lactic Acid, Calcium Signaling, Mice, Rats, Calcium Ionophores, Primary Cell Culture
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