Ménage à Trois: The Role of Neurotransmitters in the Energy Metabolism of Astrocytes, Glutamatergic, and GABAergic Neurons

Abstract

This work is a computational study based on a new detailed metabolic network model comprising well-mixed compartments representing separate cytosol and mitochondria of astrocytes, glutamatergic and gamma aminobutyric acid (GABA)ergic neurons, communicating through an extracellular space compartment and fed by arterial blood flow. Our steady-state analysis assumes statistical mass balance of both carbons and amino groups. The study is based on Bayesian flux balance analysis, which uses Markov chain Monte Carlo sampling techniques and provides a quantitative description of steady states when the two exchangers aspartate-glutamate carrier (AGC1) and oxoglutarate carrier (OGC) in the malate-aspartate shuttle in astrocyte are not in equilibrium, as recent studies suggest. It also highlights the importance of anaplerotic reactions, pyruvate carboxylase in astrocyte and malic enzyme in neurons, for neurotransmitter synthesis and recycling. The model is unbiased with respect to the glucose partitioning between cell types, and shows that determining the partitioning cannot be done by stoichiometric constraints alone. Furthermore, the intercellular lactate trafficking is found to depend directly on glucose partitioning, suggesting that a steady state may support different scenarios. At inhibitory steady state, characterized by high rate of GABA release, there is elevated oxidative activity in astrocyte, not in response to specific energetic needs.