Introduction
The predominant function of the retina is to transmit light impulse–converted nerve signals from the retina to the brain, thereby forming an interpreted image. Light waves initially enter the outer part of the eye (cornea, pupil, lens, and vitreous) to reach the retina. In the retina, the waves are converted into nerve signals mediated by the photoreceptor cells in the outer retina. These cells synapse with bipolar cells, spanning from the outer plexiform layer to the inner plexiform layer of the retina. In the inner retina, bipolar cells synapse with retinal ganglion cells, which transfer nerve signals through its axons that form the optic nerve, to the lateral geniculate nucleus of the brain, and then to the visual cortex. Thus, neuronal interactions are crucial for facilitating visual function.
To ensure neuroprotection of the innermost neurons, the most abundant retinal glial cells, Müller glia, offer several protective properties ( Fig. 12.1 ). Müller glia are located between retinal vessels and neurons and provide a buffering capacity by taking up excessive glutamate from the synapses to prevent excitotoxic damage of neurons, in particular retinal ganglion cells. These excess amounts of glutamate are taken up primarily by the vast representation of the glutamate transporter, excitatory amino acid transporter (EAAT) 1, on the cell surface. Once entering the Müller glia, the enzyme glutamine synthetase (GS) detoxifies glutamate and ammonia into glutamine, which can be shuttled back to neurons. Alternatively, glutamate may also be used as an energy substrate within the Müller glia mitochondria. Energy for excitatory glutamatergic synaptic transmission in the mammalian retina, as elsewhere in the central nervous system (CNS), is most commonly provided by the metabolism of blood-borne glucose. In fact, retinal preparations become synaptically silent as a result of glucose depletion. From an ultrastructural point of view, the remarkable concentration of mitochondria in synaptic terminals of axons indicates that glutamatergic synapses have high capacity for oxygen consumption and are major users of metabolic energy.
Metabolic energy may be provided actively by transformation and transfer of energy substrates directly from Müller glia to neurons or indirectly by Müller glia regulation of retinal blood flow. Müller glia are an integrated part of the blood-retinal barrier (BRB) and offer structural support of the retina, in particular the retinal ganglion cells and their axons. Owing to the close relation to the retinal blood vessels, Müller glia are also responsible for controlling transfer of energy substrates and other molecules to and from retinal neurons and the blood supply. Additionally, Müller glia play a prominent role in regulating the actual supply of these molecules by neurovascular coupling, in which Müller glia dilate or constrict the vasculature supporting the inner retina.
The vasculature of both the retina and brain can autoregulate, meaning that blood flow changes in response to neuronal activity (see Chapter 11 ). Glial cells, such as the Müller glia, sense neuronal activity and alter blood flow accordingly by communicating directly with the inner retinal vasculature. Thus, stimulation of retinal whole-mounts by light or direct glial stimulation has been shown to lead to either vasoconstriction or vasodilation of inner retinal blood vessels. In particular, these vascular caliber changes were found to be associated with increases in intracellular calcium within the retinal glia. Therefore, like their counterparts in the brain, retinal glia induce caliber changes in capillaries in response to neuronal activity.
Glia also communicate with each other via increases in intracellular calcium in the form of a calcium wave propagating from one astrocyte to another via gap junctions or by releasing bursts of extracellular adenosine triphosphate (ATP). Studies in retinal whole-mounts have shown that transmitters released from neurons induce transient elevations in intracellular calcium in glia. Mechanical, chemical, and light stimulation can evoke increases in intracellular calcium in both astrocytes and Müller glia that propagate to neighboring glia as a “wave.” Extracellular ATP evokes large increases in intracellular calcium in both astrocytes and Müller glia, which subsequently causes these cells to release ATP extracellularly in response to stimulation. The source of the calcium elevations in retinal glia is thought to be primarily from intracellular calcium stores, although there are also a number of calcium permeable channels, pumps, and exchangers that can mediate calcium influx to the glia from the environment.
The functional significance of ATP release and the subsequent elevation in intracellular calcium within retinal glia is twofold: direct modulation of neurons and alteration of vessel caliber.
Many types of retinal neurons are known to express ATP receptors (called P2 receptors), including photoreceptors, amacrine cells, and retinal ganglion cells. Moreover, photoreceptor function is modulated by extracellular ATP. Therefore, it is possible that the release of ATP extracellularly by glia could in turn modulate a variety of neuronal cell types from photoreceptors to retinal ganglion cells. With respect to glial-dependent modulation of vessel caliber, increases in intracellular calcium in cortical astrocyte endfeet are linked to marked vasodilation in the adjacent arteriole, suggesting a relationship between astrocytes and the vasculature within different regions of the CNS in response to an increase in neural activity.
Thus, glia play a crucial role not only in maintaining normal neuronal function but also in ensuring adequate retinal blood flow. Similarly, the function of glial cells can be affected by alterations in blood flow, which is known to change during systemic stress or disease.
In addition to regulating blood flow and transferring various substrates, Müller glia also produce and secrete various neurotrophic factors that support neuronal survival, e.g., neutrophins, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and glial cell–derived neurotrophic factor (GDNF). Coculture studies of Müller glia and retinal ganglion cells have also verified that the mere presence of Müller glia ensures retinal ganglion cell survival by regulating various processes. These processes include neurite formation, and protection against high glucose exposure, glutamate excitotoxicity, and nitric oxide (NO) neurotoxicity, which further highlights that Müller glia are crucial for inner retinal function.
A recent coculture study further established that the protective effect of Müller cells on retinal ganglion cell survival was abolished once Müller cell mitochondria were inhibited, indicating that Müller cell energy metabolism is important in providing the protection of retinal ganglion cells. Overall, dysfunctional glial cells, especially Müller cells, are likely to be a trigger for neuronal death due to altered energy metabolism and/or mitochondrial function leading to disrupted retinal function.
Retinal energy metabolism
The general energy substrates consist of carbohydrates, lipids, and amino acids, where the carbohydrates in the form of glucose are attributed to being the most prevalent energy source for the retina. The first step in glucose metabolism is by glycolysis, where two ATP molecules and two pyruvate or lactate molecules are produced. In 1972, Krebs et al. established that the eye, and especially the retina, is highly glycolytic and that lactate release from the eye exceeds that from the brain.
This is supported by reported elevated retinal lactate levels between 5 and 50 mmol/L compared with only 1 to 2 mmol/L in the peripheral blood of healthy humans. In particular, the Müller glia contribute to this high glycolytic rate with a favorable conversion of glucose into lactate rather than pyruvate, despite sufficient oxygen availability, a phenomenon known as the Warburg effect.
Recent studies have suggested that Müller glia may shift from glycolysis to oxidative phosphorylation during excessive stress, such as hypoglycemia and oxidative stress, indicating that mitochondrial metabolism in Müller glia may be equally important as glycolysis. In addition to producing pyruvate or lactate as the end product of glycolysis, nicotinamide adenine dinucleotide (NAD+) is also produced. NAD+ production is essential to facilitate well-functioning mitochondria, as it cofactors multiple steps in the tricarboxylic acid cycle (TCA), by which the majority of ATP is yielded.
Although electrophysiological evidence shows that neurotransmission through the inner retina is supported by glycolysis, there is currently no clear experimental evidence showing that synaptic activity of pre- and postsynaptic retinal neurons is directly sustained by glucose. However, indirect evidence is suggested from the classical work of Lowry et al. on the distribution of enzymes of glucose metabolism determined from pure samples of each retinal layer from monkey and rabbit. A brief introductory overview of this particular paper is given further as it provides invaluable insight into the contribution of Müller glia to overall retinal function and energy metabolism.
All enzymes of glycolysis are in the cytoplasm rather than in the mitochondria. To initiate glycolysis, hexokinase irreversibly phosphorylates glucose to glucose-6-phosphate (G6P). The distribution of hexokinase was confined to the layer containing inner segments of photoreceptors, the inner synaptic layer and to the innermost retinal layer bordering the vitreous. The second step in glycolysis is the conversion of G6P to fructose-6P by glucose-phosphate isomerase. The distribution of this enzyme was largely confined to the inner and outer synaptic layers. Phosphofructokinase, the third enzyme in glycolysis, irreversibly phosphorylates fructose-6P to fructose-1,6diP, and its distribution was confined to both synaptic layers and the innermost retinal layer. The ninth enzyme in glycolysis, phosphoglyceromutase, converts 3-phosphoglycerate to 2-phosphoglycerate, and its distribution was similar to that of phosphofructokinase.
In tissues with adequate oxygen supply, pyruvate formation is the 11th and final step of glycolysis. The metabolism of pyruvate for energy production consumes oxygen and completes the breakdown of glucose to CO 2 and water through the process of oxidative metabolism. Upon careful examination, the distribution of the aforementioned glycolytic enzymes corresponds to the morphologic position of Müller glia in situ. Müller glia extend radially through all of the retinal layers from the photoreceptor inner segments to the inner limiting membrane bordering the vitreous, and they extend fine filaments laterally in both synaptic layers. As mentioned previously, they also form an additional physical and functional cell layer for the diffusion of substances from the blood to neurons. Kuwabara and Cogan undertook the first comprehensive histochemical study to identify Müller glia as the primary glucose-utilizing cells in the retina. However, Müller glia are also known to utilize lactate. In fact, they have a preferred metabolism of lactate, even when glucose is present (see Fig. 12.8 ). This was thought to occur in order to spare glucose for neurons, but retinal ganglion cells in culture have also been shown to metabolize lactate before glucose. However, the notion of preferential lactate metabolism in the presence of glucose is still controversial and needs to be validated by in vivo studies. Müller glia have been shown to switch their metabolic state from glycolysis to oxidative phosphorylation during stress. Certain cells, including neurons, are known to release lactate during stress, thus Müller glia uptake of lactate for oxidative phosphorylation may provide a rapid metabolic production of ATP by passing glucose breakdown to pyruvate, which involves more steps.
Regardless of how the energy consumption of the retina (or other parts of the CNS) is altered locally to meet changing demands, it is important to know from a neurophysiological point of view which cell types and what cellular events are associated with local changes in blood flow, metabolism, and tissue oxygenation.
Retinal oxygen distribution and consumption
Under normal conditions, O 2 is the limiting factor in retinal metabolism. Oxygen is used by mitochondria and their distribution is important for understanding locations of high O 2 demand. The O 2 consumption (QO 2 ) of the retinal pigment epithelial (RPE) cells is about 20% of that of the retina per mg protein. Mitochondria are densely observed in the inner segments (IS) of photoreceptors. Cones have more mitochondria than rods. Mitochondria are also found in each rod spherule and cone pedicle. In the inner retina, the inner plexiform layer has a larger number of mitochondria than the nuclear layers.
The human retina has a complex vascular supply system to ensure adequate oxygenation. The inner retina is nourished by the retinal circulation, while the outer retina is supplied by the choroidal vasculature. Just as in the brain, the retina has a continuous demand for oxygen and, as such, a lack of oxygen supply will be associated with hypoxia leading to retinal disease.
Using dual-beam bidirectional Doppler optical coherence tomography, the total retinal blood flow was 44.3 ± 9.0 μL/min at baseline and decreased to 18.7 ± 4.2 μL/min during 100% oxygen breathing, resulting in a pronounced decrease in retinal oxygen extraction from 2.33 ± 0.51 μL(O 2 )/min to 0.88 ± 0.14 μL(O 2 )/min during breathing of 100% oxygen, a known hyperoxic state.
The inner retina
The distribution of oxygen tension (P o 2 ) close to the vitreoretinal interface is heterogeneous, being higher close to the arteriolar wall. Preretinal and transretinal P o 2 profiles indicate that O 2 diffusion from the arterioles affects the P o 2 in the juxta-arteriolar areas ( Fig. 12.2 ). O 2 reaches the vitreous by diffusion from the retinal circulation. In contrast, far from the vessels, the preretinal P o 2 remains constant and the average preretinal P o 2 from the vitreal side is similar to that measured in the inner retina. In the inner retina, P o 2 averages about 20 mmHg, but up to 60 mmHg close to the arteriolar wall.
Dark and light O 2 consumption
Inner retinal oxygen consumption has been shown to be the same in light and darkness, indicating no influence of light adaptation as there is in the outer retina. In the inner retina, retinal ganglion cells have much higher firing rates if a stimulus is presented repeatedly than if the same amount of light is delivered as a steady background. Consequently, one would expect the inner retina to use more energy when a stimulus is flickering. Indeed, there is, in response to a flickering stimulus, a higher lactate production in the inner retina of rabbit than during darkness or steady illumination and a higher deoxy- d -glucose uptake in monkey retina.
The outer retina
Transretinal P o 2 measurements have provided data about the O 2 supply to the photoreceptors and their QO 2 . P o 2 profiles made in cat, pig, and monkey indicate that oxygen diffuses from the inner retina and from the choroid toward the middle of the retina, i.e., the outer plexiform layer (OPL). The choroidal circulation supplies about 90% of the photoreceptor’s O 2 use.
Photoreceptor QO 2 in darkness
In the dark-adapted retina, photoreceptor QO 2 (Q OR ) depends strongly on choriocapillary P o 2 in cat and monkey. In the IS of photoreceptors the local value of QO 2 is about five times higher than in the outer segments (OS). A similar range for QO 2 in the outer retina was obtained in rat, rabbit, and pig retinas. In both cat and monkey, the average value of P o 2 in the choriocapillaries is about 50 mmHg, and the corresponding average value of QO 2 in the outer retina is 4 to 5 mL O 2 /100 g −1 per min −1 .
The average P o 2 value in cat was 5 mmHg; the minimum was frequently indistinguishable from zero in the dark, as predicted by Dollery et al. The amount of oxygen consumed is an indirect measure of ATP synthesis and thus of ATP utilization. The ATP produced in the dark fuels many cellular processes, mainly the Na + /K + -ATPase in the IS, which extrudes a large amount of sodium that enters through the light-dependent channels in the OS. An additional process is the turnover of Cyclic guanosine monophosphate (cGMP) that holds these channels open.
As noted previously, there is no evidence about whether individual rods and cones use different amounts of O 2 . Cones in the primate fovea appear to use slightly less O 2 than the parafoveal photoreceptors.
Photoreceptor QO 2 in light
QO 2 in the outer retina is lower in steady light than in darkness in various animals investigated. The activity of the Na + /K + -ATPase decreases in light, but the turnover of cGMP increases, so the decrease in Q OR is not as great as the decrease in the pump rate. The maximum size of the overall change appears to be species dependent.
The role of glycolysis underlying retinal function: from whole retina to its parts
Visualization of dynamic functional activity in the retina is an indirect measurement of neuronal activity. It is important to appreciate that any dynamic “functional imaging” of the CNS, for example, functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) imaging, measures local changes in brain metabolism and physiology that are associated with neuronal activity. Therefore, examining and evaluating retinal function necessarily involves understanding the energy metabolism of this particular tissue.
The significance of glucose and its metabolism through the glycolytic pathway in mammalian retina is attested by the measured high rate of aerobic glycolysis in vitro (high capacity for oxygen consumption), its susceptibility to iodoacetate, a strong Pasteur effect (inhibition of glucose utilization), and the aerobic and anaerobic production of lactate.
The adult retina, as is the case for every CNS region, depends on an uninterrupted supply of blood-borne glucose. Under normal conditions, glucose is virtually the main substrate supporting the intense energy metabolism required to maintain retinal function, (e.g., normal electrical responsiveness to light and neurotransmission). Lactate generated from either anaerobic glycolysis or glycogenolysis within the retina has recently been proposed as another important energy source during synaptic transmission. but its uptake and metabolism by retinal cells has yet to be demonstrated in vivo. Nevertheless, a recent study found significantly lower peripheral blood lactate levels in glaucoma patients with well-defined retinal neurodegeneration, implying that diminished or dysfunctional lactate turnover may contribute to obscured retinal health.
The distribution of key enzymes in glucose metabolism through the individual neuronal and synaptic retinal layers and the dehydrogenases for several of the intermediate stages of glucose degradation in retina have been documented in a series of pioneering histochemical work.
Metabolic studies have demonstrated that Müller glia both in situ and when acutely isolated, preferentially and massively take up and phosphorylate glucose, part of which is stored as glycogen. Further evidence to confirm this finding has been performed in vivo.
More supporting evidence comes from the use of iodoacetate, a well-known glycolytic poison which exerts its effect when the transformation of glucose is committed to proceed through glycolysis. In the 1950s, it was shown that intravenous delivery of sodium iodoacetate in rabbit, monkey, and cat abolished the electrical response of the visual pathway to illumination within minutes, with a resulting histologic picture similar to that presented in human retinitis pigmentosa. This led to the speculation that the initial effect must be on visual cells, although Warburg suggested that the different cell types in the retina may not contribute equally to the general biochemical picture. Indeed, this suggestion has been unambiguously supported by the differential suppression of the component waves of the extracellular electroretinogram (ERG). However, beyond this evidence, the identity of the retinal cell types taking up iodoacetate remains unknown. Recently this was explored using synchrotron-based x-ray fluorescence of iodoacetate at the cellular level in situ ( Fig. 12.3 ). The fluorescence map ( Fig. 12.3A ) generated from the dark-adapted retina ( Fig. 12.3B ) showed that iodoacetate was taken up specifically by Müller glia and not by retinal neurons, including photoreceptors, indicating that the effect of iodoacetate on neurons is not direct but secondary to inhibiting glycolysis in glia (Poitry-Yamate unpublished data ). Together, these results suggest a key role played by Müller glia in transporting glucose from the blood into the retina. Müller glia have also been shown to take up lactate, which is then metabolized and used as an additional energy source. In addition, Müller glia secrete lactate, which can be taken up and processed by surrounding neurons, e.g., photoreceptors and retinal ganglion cells.
Acutely isolated mammalian photoreceptors produce 14 CO 2 from 14 C(U)-glucose, whereas photoreceptor OS produce both lactate from glucose and 14 CO 2 from 14 C(U)-glucose. The results have been interpreted as indicating that both glycolysis and the pentose phosphate pathway contribute to photoreceptor function. Given that only one in six carbons from 14 C(U)-glucose is converted to 14 CO 2 through the pentose phosphate pathway, and the abundance of photoreceptor mitochondria, 14 CO 2 is likely to reflect the rate of mitochondrial respiration.
Photoreceptors of some species do not express Gpi 1, the enzyme catalyzing the isomerization of glucose-6-phosphate to fructose-6-phosphate, leaving the phosphate pentose pathway as the only possible downstream path, with a gain of two NADPH molecules potentially serving as a reducing agent for reduction of retinaldehyde.
A number of studies of glucose metabolism have been undertaken in intact retinal tissue or with acutely isolated cell models in vertebrate/mammalian retina. Of these, one is unique in studying not only glucose metabolism but also metabolic compartmentation: the cell model of acutely isolated Müller glia still attached to photoreceptors (termed “the cell complex”) shown in Fig. 12.4 and further discussed in sections Biochemical specialization of glial cells, Functional neuronal activity and division of metabolic labor, and Experimental models of retinal metabolism and function, in this chapter. This study confirmed not only the previous work by Kuwabara and Cogan, but showed for the first time in a mammalian preparation of the CNS tissue that glial cells transform rather than simply transfer the primary energy substrate glucose, and supply neurons with a glucose-derived metabolite.
Cell culture models of transformed rat Müller glia, human RPE, and transformed mouse photoreceptor cells and retinal ganglion cells were all found to produce lactate, aerobically and anaerobically, in the presence of 5 mM glucose. This may not be surprising as culturing techniques influence cell metabolism and function. The composition of culturing medium may be a key underlying factor to explain why cells are predominantly glycolytic, irrespective of cell type. However, the production of lactate by these cells did not significantly differ with the addition of 10 mM lactate. In general, lactate production and its release into the extracellular space as a lactate anion plus a proton (H + ) creates an extracellular pH gradient, i.e., increased proton concentration and consequently pH values become less than 7.4. Depending on the magnitude, direction, and time course of the extracellular pH gradient, lactate may accumulate extracellularly, or alternatively, lactate may be taken up on a proton-linked monocarboxylate transporter. In this context, both cultured retinal ganglion cells and freshly isolated retinas from mice have revealed lactate uptake and metabolism. In addition, metabolic studies using gas-chromatography mass spectrometry have shown preferential uptake and metabolism of lactate in Müller glia and retinal ganglion cells, even in the presence of glucose. Taken together, these cells may act as buffers of lactate in the extracellular environment, thereby securing adequate pH levels.
Biochemical specialization of glial cells
As previously outlined, Müller glia (also termed radial fibers or sustentacular cells of Heinrich Müller) are the major glial cell type in vertebrate retina. Structurally, Müller glia are elongated, possess a prominent specialized region called endfeet at the inner limiting membrane, and are vertically oriented with respect to the retinal layers ( Fig. 12.5 ). As Müller glia extend through the synaptic and nuclear layers of the retina from the inner to outer limiting membranes, they are in intimate apposition to every neuron cell type. Müller glia also serve as an additional physical and functional cell layer to the diffusion of substances into and out of the extracellular space, the vitreous, the subretinal space, and retinal vascular supply. Histochemical evidence has shown that glycogen synthesis, glycogenolysis, and anaerobic glycolysis are localized to Müller glia in situ. This was confirmed and quantitated in living, intact, dark-adapted retina using biochemical and autoradiographic methodologies, and provided strong experimental evidence for the working hypothesis of all retinal cell types, that is, that Müller glia play a major role beyond the blood-retinal barriers in transporting glucose from the blood into the neural retina. However, once in the neural retina, it remains to be shown along the entire radial length of Müller glia whether the distribution of transporters related to energy substrate uptake and release are tailored to this cell’s own metabolic needs, yet adapted to the function and metabolic needs of their immediate neuronal environment.
Two functional and biochemical specializations unique to Müller glia are their capacity to inactivate the excitatory neurotransmitter glutamate and inhibitory neurotransmitters GABA and glycine. They are the exclusive and/or predominant cellular site of:
- 1.
GS activity for the synthesis and release of glutamine, a precursor for photoreceptor neurotransmitter resynthesis ; and
- 2.
carbonic anhydrase for the conversion of water and CO 2 of neuron origin to bicarbonate, an enzymatic activity implicated in the regulation of intracellular and extracellular pH and volume.
Role of glycogen
As an endogenous source of glucose-6-phosphate, glycogen, as well as glycogen phosphorylase, is exclusively localized to the cytoplasm of Müller glia in situ in a variety of mammalian species. This important finding suggests that Müller glia can effectively mobilize this energy store, but it remains unclear whether it is for the purpose of meeting their own energy needs or, alternatively, partly those of the surrounding neurons in the form of lactate generated via glycogenolysis. One isoform of glycogen phosphorylase is expressed in cone photoreceptors (brain type), and another isoform (muscle type) is expressed in the inner plexiform synaptic layers of primate retina. So, although glycogen metabolism in Müller glia is established, the function of Müller glia glycogen is still far from clear. The prevailing view is that glycogen plays the role of an emergency retinal carbohydrate reservoir supporting neuron function when glucose delivery is compromised, such as during retinal ischemia. This contrasts with another view that Müller glia glycogen is mobilized as an immediate and accessible energy store under normal physiologic conditions ( Fig. 12.6 ), such as changes in illumination, that is, light and darkness, and which are linked to the direct effects of altering photoreceptor function. In addition, glycogenolysis can be stimulated in the retina by neurotransmitters increasing Cyclic adenosine monophosphate (cAMP), such as vasoactive intestinal peptide, which are contained in and released from amacrine cells. In the context of cAMP, lactate has also been shown to play a role. Hence, lactate acts as a ligand of the Hydroxycarboxylic acid receptor 1 (HCAR1), which induces a Gi-mediated pathway that results in decreased cAMP. In turn, this leads to reduced glycogenolysis, thereby triggering the cells to utilize lactate prior to glucose stored as glycogen, thereby potentially sparring glucose for neurons. Glycogen is also localized in neurons of the cat retina, particularly of the rod-driven pathway, the rod-driven components of which are selectively sensitive to prolonged hypoglycemia, but whether this glycogen is mobilized is not presently known.
Functional neuronal activity and division of metabolic labor
A continuous supply of blood-borne glucose is vital to maintaining retinal function but does not necessarily dictate that all retinal cells (both neurons and glia) take up and metabolize this energy substrate as is generally believed. Indeed, the conventional view of glucose metabolism in CNS is that glucose is the principal substrate for oxidative metabolism in both cell types, i.e., neurons and glia. The experimental evidence described in the previous sections is a major departure from this view and raises three highly controversial and still unresolved questions about the brain and about the generality of the findings in retina to other parts of the CNS:
- 1.
Is glucose, the major brain energy substrate, taken up in a cell type–specific manner?
- 2.
Does glycolysis predominate in one particular cell type, physiologic condition, or brain region and oxidative metabolism of glucose in another? and
- 3.
Does coupling of metabolic and physiologic changes to changes in neuronal activity involve the transformation of blood glucose by glial cells and do they supply neurons with glucose-derived metabolite(s)?
Underlying these issues is the idea of a predominant division of metabolic labor between neurons and glia. In other words, energy substrate production and substrate use are partitioned in a relatively cell-specific manner. This working hypothesis, summarized in Fig. 12.7 , was developed and tested in retina in the mid-1990s in insect and mammal, and has seen a revival in the recent decade, particularly with regards to the recognition that the coordinated action of glial cells and neurons extends to energy metabolism throughout the CNS.
