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 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.
Highlights
One major focus of neuroenergetics research is directed towards the interactions between neuronal and glial cells, the major cellular constituents of the central nervous system
We found that a value around the low-end of 60 Na+ per glutamate correctly reproduces the experimental relationship between the rates of glutamate-glutamine cycle and neuronal oxidative metabolism (Fig. 1a)
Simulations performed with various neuronal voltage/ligand-gated Na+/K+ influx/efflux ratios largely determined the degree of astrocytic activation, which is completely abolished when the ratio is close to 3/2 (Fig. 1b)
Summary
One major focus of neuroenergetics research is directed towards the interactions between neuronal and glial cells, the major cellular constituents of the central nervous system. Neurochem Res (2017) 42:202–216 and their dependence on substrate and energy availability [1, 2] These constraints involve delicate balances between substrate supply and demand within specialized cellular metabolic networks counting dozens of coupled biochemical reactions. Standard as well as probabilistic stoichiometric models have been applied to the study of compartmentalized brain energy metabolism [4,5,6,7,8,9,10,11,12,13,14] These works have provided valuable insights into specific aspects of neuronastrocyte interactions, none have incorporated explicit pathways involved in ion homeostasis (i.e. pumps and channels) related to neurotransmission (see discussion in [6]). In the present work we overcame this limitation by taking into account ionic movements across brain cells and the associated energy demand
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