A Simulation Study of the Metabolism and Compartmentation in Brain of Glutamate, Aspartate, the Krebs Cycle, and Related Metabolites

Abstract 1. The portion of brain metabolism involving glutamate, aspartate, glutamine, glutathione, γ-aminobutyric acid, Krebs cycle intermediates, and related substances has been simulated with a digital computer. This involves the interaction of a complex metabolic pattern with a complex compartmentation. A model has been constructed from 49 differential equations representing 49 (unlabeled) chemical species, and its behavior has been compared, with generally satisfactory agreement, with experimental data obtained from administration of several 14C-labeled tracers and intravenous infusion of large doses of 15NH3. 2. Most of the substances and pathways involved in the model are divided between a large and a small compartment (except glutamine and ammonia). The large compartment contains 4 to 10 times as much as the small compartment of nearly all divided substances; but the Krebs cycle flux and hence the number of mitochondria are about equally divided between the compartments. Radioactivity from 14C-glucose first appears mostly in the large compartment, and ordinarily most CO2 fixation to oxalacetate takes place there; but high ammonia levels stimulate fixation of CO2 into the small compartment, together with an efflux of glutamine from the brain. 3. On the basis of the rates at which they metabolize possible energy sources, such as glucose, and their response to ammonia intoxication, it is suggested that the compartments serve as a homeostatic mechanism to protect part of the brain against fluctuations in environment. 4. Based on known biochemical properties, an identification with these compartments of several cytological structures is suggested: the small compartment contains the nerve ending fraction and some glial cells; the large compartment includes most of the neuron bodies and glial cells, particularly astroglia. 5. A number of experiments suggested by the model are described, mostly to check the identification of the nerve ending fraction as part of the small compartment (e.g. by following CO2 fixation in vitro). Some are to check theories relating to this area of metabolism, such as a possible neurotransmitter action of γ-aminobutyric acid.