Energy Metabolism Glucose

In the brain, astrocytes are situated in a key position between microvessels, neurons, and oligodendrocytes (Fig. 1). If one considers the narrow extracellular space between brain cells, it appears that the substrates for the generation of energy must cross the astrocytes to reach their metabolic destination in neurons. Glucose

Figure 3 Metabolic coupling between neurons and astrocytes at glutamatergic synapses. Presynaptically released glutamate depolarizes postsynaptic neurons by acting at specific receptor subtypes. The action of glutamate is terminated by an efficient glutamate-uptake system located primarily in astrocytes. Glutamate is cotransported with Na+, leading to activation of the astrocyte Na+/K+-ATPase, which in turn stimulates glycolysis (i.e., glucose utilization and lactate production). Lactate, once released by astrocytes, can be taken up by neurons and serve them as an adequate energy substrate. In accord with recent evidence, glutamate receptors are also shown on astrocytes. Glycogenolysis is also a source of lactate by glycogenolysis to glucose-6-phosphate (G6P), followed by steps of glycolysis. Direct glucose uptake into neurons under basal conditions can also occur. (adapted from Magistretti et al., 1999).

Figure 3 Metabolic coupling between neurons and astrocytes at glutamatergic synapses. Presynaptically released glutamate depolarizes postsynaptic neurons by acting at specific receptor subtypes. The action of glutamate is terminated by an efficient glutamate-uptake system located primarily in astrocytes. Glutamate is cotransported with Na+, leading to activation of the astrocyte Na+/K+-ATPase, which in turn stimulates glycolysis (i.e., glucose utilization and lactate production). Lactate, once released by astrocytes, can be taken up by neurons and serve them as an adequate energy substrate. In accord with recent evidence, glutamate receptors are also shown on astrocytes. Glycogenolysis is also a source of lactate by glycogenolysis to glucose-6-phosphate (G6P), followed by steps of glycolysis. Direct glucose uptake into neurons under basal conditions can also occur. (adapted from Magistretti et al., 1999).

is the main energy source in the CNS; although neurons are able to take up glucose and phosphorylate it, at a basic level the tight coupling between the function and the energy metabolism of this cell type requires astrocytes (Fig. 3). First there is a transport of glucose into astrocytes by specific transporters; gap junction permeability also controls the uptake and distribution of glucose in astrocytes and in this way may regulate brain metabolism. Glycogen is also a source of energy in the brain, in which it is localized almost exclusively in astrocytes, to an extent that it can be considered a marker for this cell type. Its level is finely tuned by synaptic activity. Glycogenolysis is also activity dependent. Several neurotransmitters, such as noradrenaline, serotonin, histamine, the vasoactive intestinal peptide, and the purine adenosine, promote glycogenolysis as shown in studies of slices from different brain areas. The glucosyl residues of glycogen appear to also be broken down to lactic acid.

The discovery that glucose is taken up by glial cells was first demonstrated in the CNS model of the honeybee drone retina, in which an analog of glucose [2-deoxyglucose (2-DG)] was quantitatively shown to be taken up and phosphorylated by hexokinase in glial cells during light stimulation. The same coupling also occurs in the mammalian retina. It has been demonstrated in culture of astrocytes that glutamate stimulates 2-DG uptake and phosphorylation and that there is a tight coupling between Na + -dependent glutamate uptake and glucose utilization (Fig. 3). Noradrenaline and arachidonic acid also stimulate glucose uptake by astrocytes.

There is mounting evidence that lactate, resulting from the glycolytic processing of glucose in astrocytes, is the preferred energy source for neurons, particularly during situations of high energy demand. In astrocyte cultures, there is a glutamate-evoked lactate release that correlates with glutamate-evoked glucose utilization, indicating the role of glycolysis in this process. A similar process is observed in preparations of freshly isolated Muller cells still attached to photoreceptors, even in the presence of millimolar concentrations of glucose. When such a preparation is maintained in darkness to stimulate neurotransmitter release, lactate derived from glial glycolysis is transferred from Muller cells to photoreceptors, where it serves to fuel mito-chondrial oxidative metabolism and possibly the resynthesis of the neurotransmitter pool of glutamate. There is a saturable lactate transporter in neurons. Pyruvate gives rise to lactate in astrocytes through a different lactate dehydrogenase enzyme than that in neurons; thus, there is evidence for an astrocyte-neuron lactate shuttle. In astrocytes, lactate could also be released from the metabolism of amino acids such as glutamate.

In human, glucose metabolism can be studied using (18F) fluoro-2-deoxyglucose (FDG) by positron emission tomography (PET). FDG-PET imaging supports the notion that astrocytes markedly contribute to the FDG-PET signal; this view does not challenge the validity of the 2-DG-based techniques to monitor neuronal activation since the uptake of the tracer into astrocytes is triggered by a neuronal signal (i.e., the activity-dependent release of glutamate).

Although there is no proposal for other neurotrans-mitters, the well-studied model proposed for glutama-tergic synapse can be extended to other neuro-transmitters systems, such as the primary inhibitory transmitter g-aminobutyric acid (GABA) that flows in a similar neurotransmitter cycle between neurons and astrocytes.

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