title: 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.
abstract: 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 by13C-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.
authors.affiliation: Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 24.2.40, 2200, Copenhagen N, Denmark. mauro.dinuzzo@sund.ku.dk.
authors.forename: Mauro
authors.identifier: http://orcid.org/0000-0003-0181-5597
authors.initials: M
authors.lastname: DiNuzzo
authors.affiliation: Museo Storico della Fisica e Centro Studi e Ricerche "Enrico Fermi", Rome, Italy.|Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Giove
authors.affiliation: Museo Storico della Fisica e Centro Studi e Ricerche "Enrico Fermi", Rome, Italy.|Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maraviglia
authors.affiliation: Center for Magnetic Resonance Research, Department of Radiology, Univeristy of Minnesota, Minneapolis, MN, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mangia
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D019295:Computational Biology; D004734:Energy Metabolism / Q000502:physiology*; D005544:Forecasting; D018698:Glutamic Acid / Q000378:metabolism*; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D011188:Potassium
keywords: Brain energy metabolism; Constraint programming; Flux balance analysis; Neuron-astrocyte interactions; Potassium