Schematics of the model. The figure shows selected pathways linking the four compartments of the model (capillary, interstitium or extracellular space, neuron, astrocyte). Nutrients from the blood capillary have to traverse endothelium and basal lamina (these elements have been lumped together with the capillary) to enter the brain parenchyma. Thus, arrows connecting directly capillary and cell interior represent flows across basal lamina after endothelium. Note that this shortcut makes sense for the diffusion of oxygen to neurons and astrocytes, as well as for the transport of glucose to the astrocytic compartment only. Indeed, astrocytes but not neurons are in close apposition to cerebral blood vessels. Most of the nutrients delivery to the brain occurs through interstitial space, which is therefore the primary common element for intercellular metabolite trafficking. Once into the cells, glucose (GLC) is metabolized via glycolysis to pyruvate (PYR), which can be either reduced to lactate (LAC) or further oxidized in the cell TCA cycle requiring oxygen (O2). Neuronal glutamate (GLU) is sequestered by the TCA cycle at the level of alpha-ketoglutarate (AKG) and loaded into synaptic vesicles (not shown). Neurotranmission evokes the release of vesicular glutamate into the extracellular space, from where it is taken up by astrocytes and mixed with their glutamate pool. Astrocytic glutamate can either be converted to glutamine (GLN) for export to neurons or enter the TCA cycle. The entire process consumes energy due to up-regulation of astrocytic Na+/K+-ATPase and glutamine synthetase (Vcyc), as well as neuronal vesicle (re)filling. According to the minimal-constraints strategy employed in the present model, ionic fluxes in neurons via ligand- and voltage-gated ion channels and in astrocytes via Na +/K + cotransporter follows neurotransmission passively (see text). See the Supporting Information for the full details of the network structure (139 reactions among 108 different chemical species).