Development of a Model to Test Whether Glycogenolysis Can Support Astrocytic Energy Demands of Na⁺, K⁺-ATPase and Glutamate-Glutamine Cycling, Sparing an Equivalent Amount of Glucose for Neurons

Abstract

Recent studies of glycogen in brain have suggested a much more important role in brain energy metabolism and function than previously recognized, including findings of much higher than previously recognized concentrations, consumption at substantial rates compared with utilization of blood-borne glucose, and involvement in ion pumping and in neurotransmission and memory. However, it remains unclear how glycogenolysis is coupled to neuronal activity and provides support for neuronal as well as astroglial function. At present, quantitative aspects of glycogenolysis in brain functions are very difficult to assess due to its metabolic lability, heterogeneous distributions within and among cells, and extreme sensitivity to physiological stimuli. To begin to address this problem, the present study develops a model based on pathway fluxes, mass balance, and literature relevant to functions and turnover of pathways that intersect with glycogen mobilization. A series of equations is developed to describe the stoichiometric relationships between net glycogen consumption that is predominantly in astrocytes with the rate of the glutamate-glutamine cycle, rates of astrocytic and neuronal glycolytic and oxidative metabolism, and the energetics of sodium/potassium pumping in astrocytes and neurons during brain activation. Literature supporting the assumptions of the model is discussed in detail. The overall conclusion is that astrocyte glycogen metabolism is primarily coupled to neuronal function via fueling glycolytically pumping of Na⁺ and K⁺ and sparing glucose for neuronal oxidation, as opposed to previous proposals of coupling neurotransmission via glutamate transport, lactate shuttling, and neuronal oxidation of lactate.