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Figure 3.1. Pathways by which glucose (arrows) released from capillaries can end up in neurons. The first pathway does not involve the Müller cell. In the second pathway, glucose is taken up by the Müller cell and released for neuronal uptake. In the third pathway, glucose enters the Müller cell where it is converted to a metabolite, such as lactate (heavy arrows), and is released for use by neurons. In the final pathway, glucose is taken up by the Müller cell and converted to glycogen (dots) for storage; subsequently, the glycogen is broken down to glucose and released for uptake by neurons.

Figure 3.1. Pathways by which glucose (arrows) released from capillaries can end up in neurons. The first pathway does not involve the Müller cell. In the second pathway, glucose is taken up by the Müller cell and released for neuronal uptake. In the third pathway, glucose enters the Müller cell where it is converted to a metabolite, such as lactate (heavy arrows), and is released for use by neurons. In the final pathway, glucose is taken up by the Müller cell and converted to glycogen (dots) for storage; subsequently, the glycogen is broken down to glucose and released for uptake by neurons.

tion. How does glucose released from capillaries end up as carbon fuel in retinal neurons? Do Müller cells serve as an intermediary in this process?

There are several routes by which glucose released from capillaries can end up in neurons (Fig. 3.1; cf. Coles, 1996). One route would be direct transfer of glucose from capillaries to neurons without any Müller cell involvement; other routes can involve active participation of glial cells either as a conduit for glucose transfer or as a site for glucose storage and metabolism before release to neurons. At least four pathways can be invoked to describe glucose transfer (Coles, 1996; Fig. 3.1).

In pathways one and two, glucose does not undergo any change, whereas in pathways three and four glucose is converted to a metabolite in Müller cells. In the first pathway, glucose can diffuse away from capillaries and be taken up directly by neurons without intervention of Müller cells. In the second pathway, Müller cells can take up glucose from blood and redistribute it to neurons. In the third pathway, glucose taken up by Müller cells can be converted to a metabolite, which is released for use by neurons.

And in the fourth pathway, glucose can be transformed to glycogen in Müller cells and later broken down to provide glucose for neurons. These pathways are not mutually exclusive, Although none of the pathways can be ruled out completely, the available experimental evidence indicates that in the CNS, glucose is taken up by glial cells, converted to a metabolite, and subsequently released for neuronal use (Magistretti et al., 1999).

3.1.1. Glucose Uptake and Neuronal Activity

If Müller cells provide neurons with energy metabolites, they must first take up glucose in quantities sufficient for their own needs and for the retinal neurons they serve. The cellular sites of glucose uptake have been determined in a number of vertebrate retinas by autoradiographic studies using 3H-2-deoxyglucose (3H-2-DG), a nonmetabolizable analog of glucose. Early studies showed that photoreceptors are able to accumulate 2-DG (Basinger et al., 1979; Witkovsky and Yang, 1982; Sperling et al., 1982) irrespective of whether 3H-2-DG was supplied in an incubation medium or was injected intravitreally. Based on these data, it appeared glucose could be directly taken up by photoreceptors in some species.

In contrast, Poitry-Yamate and Tsacopoulos (1991; 1992) found that when isolated guinea pig retina was incubated with 3H-2-DG, labeling was confined to Müller cells; photoreceptors and other retinal neurons were not labeled. The authors further demonstrated that freshly dissociated Müller cells could take up and phosphorylate 2-DG (Fig. 3.2). This result, and evidence that the glucose transporters, GLUT1 and GLUT2, are localized to the apical processes of Müller cells (Mantych et al., 1993; Watanabe et al., 1994), are a good indication that Müller cells are capable of avidly taking up exogenous glucose.

Further support for the importance of glucose uptake comes from experiments showing that neuronal activity can stimulate glucose uptake by glial cells (cf. Tsacopoulos and Magistretti, 1996). How does the glial cell sense the energy needs of the neurons? There is growing experimental evidence that synaptically released glutamate serves as the signal that links neuronal activation and glial uptake of glucose. Pellerin and Magistretti (1994) have shown directly that the addition of 0.2 mM glutamate strongly stimulates glucose uptake by astrocyte cultures (Fig. 3.3).

Surprisingly, the action of glutamate in promoting glucose uptake does not involve glutamate receptors but is mediated by the glial glutamate transporters (Pellerin and Magistretti, 1994; Takahashi et al., 1995). Glutamate-induced glucose uptake appears not to be affected by glutamate receptor antagonists, but is inhibited by preincubating astrocyte cultures with the glutamate transport inhibitor, DL-threo-ß-hydroxyaspartate (THA) (Pel-

Figure 3.2. Glucose uptake by Müller cells. A. Chromatographic profile showing intracellular [3H] 2DG and [3H] 2DG-6P in Muller cells incubated with [3H] 2-deoxyglucose (2DG). Note that >80% of 3H-radioactivity is associated with 2DG-6P. B. Autoradiographic localization of 3H-radioactivity in a dissociated Muller cell (Poitry-Yamate and Tsacopoulos, 1992). (Copyright 1992 John Wiley & Sons, Inc., reprinted with permission.)

Figure 3.2. Glucose uptake by Müller cells. A. Chromatographic profile showing intracellular [3H] 2DG and [3H] 2DG-6P in Muller cells incubated with [3H] 2-deoxyglucose (2DG). Note that >80% of 3H-radioactivity is associated with 2DG-6P. B. Autoradiographic localization of 3H-radioactivity in a dissociated Muller cell (Poitry-Yamate and Tsacopoulos, 1992). (Copyright 1992 John Wiley & Sons, Inc., reprinted with permission.)

lerin and Magistretti, 1994). Uptake is also blocked by the Na+/K+ ATPase inhibitor, ouabain (Takahashi et al., 1995). Moreover, treatment with mon-ensin, a Na+-ionophore, was shown to stimulate 2-DG uptake into astrocytes (Yarowsky et al., 1986).

The following sequence of events has been proposed to explain how glucose uptake and utilization might be triggered by the influx of glutamate. Glutamate transport, which is coupled to the inward movement of sodium ions, results in a significant elevation in intracellular [Na+] (Kimelberg et al., 1993). The increase in [Na+]i leads in turn to activation ofNa+/K+ ATPase, resulting finally in stimulation of glucose uptake and glycolysis (Fig. 3.3). Since glutamate is the neurotransmitter released by photoreceptors (Massey, 1990), it is likely that glucose uptake into Müller cells is linked to photoreceptor synaptic activity. Is the glucose taken up by glial cells transferred to neurons or is it first converted to other substrates before transfer? The fate of glucose taken up by glial cells will be considered in the following sections.

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