Abstract

The question of the preferred substrate of glutamatergic neurons at high neural activity has been vibrantly debated for over a decade since the classical hypothesis (CH) of the primacy of glucose has been challenged by the astrocyte-neuron lactate shuttle hypothesis (ANLSH), which replaces the primacy of glucose with astrocyte produced lactate. We perform Bayesian Flux Balance Analysis (BFBA) with a new mathematical model of cellular brain energetics, comprising detailed biochemical pathways in and between astrocytes and glutamatergic neurons and partitioning of each cell type into cytosol and mitochondria. Supported by the results of our in silico studies, which are in remarkable agreement with previously published results, we posit the Glucose Shunt Hypothesis (GSH) that during high activity, the inhibition of the phosphofructokinase (PFK) enzyme in neuron impairs neuronal glycolysis, enabling the process by which lactate effluxed by astrocytes is taken up by glutamatergic neurons, whereas at low activity, glucose remains the preferred substrate for neurons. We postulate that the ANLS is a shunt utilized by glutamatergic neurons to bypass their glycolysis impaired by the inhibition of PFK in connection with increased oxidative phosphorylation at high neuronal activity.