Computational Flux Balance Analysis Predicts that Stimulation of Energy Metabolism in Astrocytes and their Metabolic Interactions with Neurons Depend on Uptake of K+ Rather than Glutamate

Mauro DiNuzzo, Federico Giove, Bruno Maraviglia, Silvia Mangia

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Brain activity involves essential functional and metabolic interactions between neurons and astrocytes. The importance of astrocytic functions to neuronal signaling is supported by many experiments reporting high rates of energy consumption and oxidative metabolism in these glial cells. In the brain, almost all energy is consumed by the Na+/K+ ATPase, which hydrolyzes 1 ATP to move 3 Na+ outside and 2 K+ inside the cells. Astrocytes are commonly thought to be primarily involved in transmitter glutamate cycling, a mechanism that however only accounts for few % of brain energy utilization. In order to examine the participation of astrocytic energy metabolism in brain ion homeostasis, here we attempted to devise a simple stoichiometric relation linking glutamatergic neurotransmission to Na+ and K+ ionic currents. To this end, we took into account ion pumps and voltage/ligand-gated channels using the stoichiometry derived from available energy budget for neocortical signaling and incorporated this stoichiometric relation into a computational metabolic model of neuron-astrocyte interactions. We aimed at reproducing the experimental observations about rates of metabolic pathways obtained by 13C-NMR spectroscopy in rodent brain. When simulated data matched experiments as well as biophysical calculations, the stoichiometry for voltage/ligand-gated Na+ and K+ fluxes generated by neuronal activity was close to a 1:1 relationship, and specifically 63/58 Na+/K+ ions per glutamate released. We found that astrocytes are stimulated by the extracellular K+ exiting neurons in excess of the 3/2 Na+/K+ ratio underlying Na+/K+ ATPase-catalyzed reaction. Analysis of correlations between neuronal and astrocytic processes indicated that astrocytic K+ uptake, but not astrocytic Na+-coupled glutamate uptake, is instrumental for the establishment of neuron-astrocytic metabolic partnership. Our results emphasize the importance of K+ in stimulating the activation of astrocytes, which is relevant to the understanding of brain activity and energy metabolism at the cellular level.

Original languageEnglish (US)
Pages (from-to)202-216
Number of pages15
JournalNeurochemical Research
Issue number1
StatePublished - Jan 1 2017

Bibliographical note

Funding Information:
This study is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No. 701635. The content is solely the responsibility of the authors and does not necessarily represent the official views of the European Union.

Publisher Copyright:
© 2016, The Author(s).


  • Brain energy metabolism
  • Constraint programming
  • Flux balance analysis
  • Neuron-astrocyte interactions
  • Potassium


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