Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex

Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA cycle rates in neurons by 12% ( math formula, p < 0.001) and in astrocytes by 24% ( math formula, p = 0.007). We further observed linear relationships between VNT and both math formula and math formula. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.

Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by (13)C Magnetic Resonance Spectroscopy

João Miguel das Neves Duarte, Freya-Merret Girault, Rolf Gruetter, Sarah Catherine Sonnay

Type 2 diabetes (T2D) is associated with deterioration of brain structure and function. Here, we tested the hypothesis that T2D induces a reorganization of the brain metabolic networks that support brain function. For that, alterations of neuronal and glial energy metabolism were investigated in a T2D model, the Goto-Kakizaki (GK) rat. (13)C magnetic resonance spectroscopy in vivo at 14.1 T was used to detect (13)C labeling incorporation into carbons of glutamate, glutamine, and aspartate in the brain of GK (n = 7) and Wistar (n = 13) rats during intravenous [1,6-(13)C]glucose administration. Labeling of brain glucose and amino acids over time was analyzed with a two-compartment mathematical model of brain energy metabolism to determine the rates of metabolic pathways in neurons and glia. Compared to controls, GK rats displayed lower rates of brain glutamine synthesis (- 32%, P

2019

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Pierre Magistretti, Luc Pellerin

Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood flow and energy metabolism. Positron emission tomography (PET) signals detect blood flow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identifies the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic fluxes in purified preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identified the neurotransmitter glutamate and astrocytes, a specific type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This effect is mediated by specific glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na+. This Na(+)-dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na+/K(+)-ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na+ ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one 'turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule. These data suggest that during activation the brain may transiently resort to aerobic glycolysis occurring in astrocytes, followed by the oxidation of lactate by neurons. The proposed model provides a direct mechanism to couple synaptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with 18F-deoxyglucose (DG)-PET may reflect predominantly uptake of the tracer into astrocytes. This conclusion does not question the validity of the 2-DG-based techniques, rather it provides a cellular and molecular basis for these functional brain imaging techniques.

1999

The cellular bases of functional brain imaging: evidence for astrocyte-neuron metabolic coupling

Pierre Magistretti, Luc Pellerin

Signals detected with functional brain imaging techniques are based on the coupling between neuronal activity and energy metabolism. Positron emission tomography signals detect blood flow, oxygen consumption and glucose utilization associated with neuronal activity; the degree of blood oxygenation is thought to contribute to the signal detected with functional magnetic resonance imaging, whereas magnetic resonance spectroscopy identifies the spatiotemporal pattern of activity-dependent appearance of metabolic in termediates, such as glucose or lactate. Despite the technological sophistication of these brain imaging techniques, the precise mechanisms and cell types involved in coupling and in generating metabolic signals are still debated. Indeed, given the level of resolution achieved with these brain imaging techniques, it has not been feasible to monitor met abolic fluxes between the highly intermingled neuronal, glial, and vascular elements in the intact brain. This obstacle has been overcome in recent years by using purified cellular preparations of neurons and glia. These approaches have suggested a critical role for astrocytes in coupling neuronal activity to energy metabolism. Indeed, astrocytes possess receptors and reuptake sites for a variety of neurotransmitters, including glu tamate. In addition, astrocytic end-feet, which surround capillaries, are enriched in the specific glucose transporter GLUT-1. These features would be expected to allow astro cytes to sense synaptic activity and to couple it with energy metabolism. During activa tion, glutamate is the predominant neurotransmitter released by modality-specific excitatory pathways to a given cortical area; in vitro and in vivo data support a model in which glutamate would stimulate, during activation, an initial glycolytic processing of blood-borne glucose by astrocytes; this glutamate-dependent process would result in a transient lactate overproduction, followed by a recoupling phase during which lactate would be oxidized by neurons. Such a model is consistent with data recently obtained with functional brain imaging techniques

1997

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Pierre Magistretti, Luc Pellerin

1999

The cellular bases of functional brain imaging: evidence for astrocyte-neuron metabolic coupling

Pierre Magistretti, Luc Pellerin

1997