An Integrated Cellular Perspective
Pierre J. Magistretti, Luc Pellerin, and Jean-Luc Martin
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Glucose is the obligatory energy substrate for brain and it is almost entirely oxidized to CO2 and H2O. This simple statement summarizes, with few exceptions, over four decades of careful studies of brain energy metabolism at the organ and regional levels, extensively reviewed elsewhere. To reflect the focus of this book, and to include recent observations made in several laboratories including our own, we provide in this chapter a key for reinterpreting brain energy metabolism with a cellular perspective. This key relies primarily on the cytological relationships and chemical interactions among the various cell types of the brain. The view that emerges from this cellular and molecular analysis is a cell-specific sequence of processes that eventually leads to the almost complete oxidation by the brain of blood-borne glucose, which is in accordance with the introductory statement. The proposed model relies on already available data; it can further be tested experimentally, and it provides an explanation for some recent unexpected data obtained by positron emission tomography (PET) and functional magnetic resonance imaging (MRI) studies in humans.
Metabolic trafficking between astrocytes and neurons. À: Synaptic activity causes an accumulation of glutamate in the synaptic cleft. Á: An astrocytic glutamate transporter ensures removal of glutamate from the synaptic cleft. Â: The entry of Na+ cotransported with glutamate activates the Na+,K+-ATPase hence decreasing ATP levels. Ã: The decrease in ATP levels activates the glycolytic flux (see Fig. 1) hence stimulating glucose uptake from the capillaries. Ä: Lactate, the major end product of glycolysis, is released by astrocytes and taken up by neurons where it can enter the TCA cycle. Other metabolic intermediates such as pyruvate and the TCA cycle intermediates malate, citrate, and a-ketoglutarate, although quantitatively less significant, may also be released. Å: Certain neurotransmitter systems such as those containing NE and VIP promote glycogenolysis hence supplying further glycosyl residues for glycolysis. N, Neuron; A, astrocyte, C, capillary; Glu, glutamate; a-KG, a-ketoglutarate; DAG, diacylglycerol; Vm, depolarization of glutamate-containing terminal.
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